Citations

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Background: Nonrheumatic valvular diseases are common; however, no studies have estimated their global or national burden. As part of the Global Burden of Disease Study 2017, mortality, prevalence, and disability-adjusted life-years (DALYs) for calcific aortic valve disease (CAVD), degenerative mitral valve disease, and other nonrheumatic valvular diseases were estimated for 195 countries and territories from 1990 to 2017. Methods: Vital registration data, epidemiologic survey data, and administrative hospital data were used to estimate disease burden using the Global Burden of Disease Study modeling framework, which ensures comparability across locations. Geospatial statistical methods were used to estimate disease for all countries, because data on nonrheumatic valvular diseases are extremely limited for some regions of the world, such as Sub-Saharan Africa and South Asia. Results accounted for estimated level of disease severity as well as the estimated availability of valve repair or replacement procedures. DALYs and other measures of health-related burden were generated for both sexes and each 5-year age group, location, and year from 1990 to 2017. Results: Globally, CAVD and degenerative mitral valve disease caused 102 700 (95% uncertainty interval [UI], 82 700–107 900) and 35 700 (95% UI, 30 500–42 500) deaths, and 12.6 million (95% UI, 11.4 million–13.8 million) and 18.1 million (95% UI, 17.6 million–18.6 million) prevalent cases existed in 2017, respectively. A total of 2.5 million (95% UI, 2.3 million–2.8 million) DALYs were estimated as caused by nonrheumatic valvular diseases globally, representing 0.10% (95% UI, 0.09%–0.11%) of total lost health from all diseases in 2017. The number of DALYs increased for CAVD and degenerative mitral valve disease between 1990 and 2017 by 101% (95% UI, 79%–117%) and 35% (95% UI, 23%–47%), respectively. There is significant geographic variation in the prevalence, mortality rate, and overall burden of these diseases, with highest age-standardized DALY rates of CAVD estimated for high-income countries. Conclusions: These global and national estimates demonstrate that CAVD and degenerative mitral valve disease are important causes of disease burden among older adults. Efforts to clarify modifiable risk factors and improve access to valve interventions are necessary if progress is to be made toward reducing, and eventually eliminating, the burden of these highly treatable diseases.

Abstract Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites >2 were associated with worse PFS (P < .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites >2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments.

Abstract To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV , 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person‐years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow‐up of 24 months, the estimated median event‐free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.

e19503 Background: The risk of venous thromboembolic events (VTE) despite mandatory thromboprophylaxis (TPx) in patients with multiple myeloma (MM) receiving contemporary lenalidomide (Len)-based regimens is not well-defined. Methods: Medline, Embase, and CENTRAL databases were queried to identify phase 1-3 clinical trials of Len-based regimens with mandatory TPx published until April 2018. Random effects meta-analysis was performed using CMAv3 software to obtain crude, and per 100 patient-cycle incidence rate (IR). Prespecified subgroup analyses were performed to obtain IR for VTE by (1) line of treatment (newly diagnosed [ND], relapsed/refractory [RR] and maintenance [Mx] phase) and (2) different Len-based regimens. Results: We screened 1069 citations and analyzed data from 43 trials with 8696 patients, including 17 in ND, 23 in RR and 3 in Mx phase. 12 out of 43 were Phase 3 randomized controlled trials. The overall incidence of VTE in 8696 patients was 4.6% (95% CI, 3.7-5.8%), with 1.0 event (95% CI, 0.7-1.4%) per 100 patient cycles. In patients with NDMM (n = 3295), 193 (5.9%) experienced VTE with a pooled IR of 0.9 (95% CI, 0.3-2.3) per 100 patient-cycle. Among RRMM patients (n = 3981), 251 (6.3%) experienced VTE with a pooled IR of 1.0 (95% CI, 0.4-2.3) per 100 patient-cycle. The incidence of VTE was highest with the following triplet regimens: Rd + Proteasome inhibitor (PIs) and Rd + Anthracycline (Ac) [+/- Vincristine], with the latter having a high risk of VTE regardless of the treatment phase (table). With Len Mx (n = 1420), 38 (2.7%) patients had VTE, with a pooled IR of 0.2 (95% CI, 0-2.1) per 100 patient-cycle. Conclusions: Patients with MM undergoing treatment with Len-based regimens remain at risk of VTE despite current TPx strategies. The estimates of VTE IR provided by this analysis can guide clinicians in assessing treatment-related risk of VTE in this setting. [Table: see text]

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts <75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (<75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for <75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both <75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10-5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (<75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in <75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]

8016 Background: MAIA, an ongoing phase 3 trial of transplant-ineligible patients (pts) with NDMM, demonstrated significant improvement in progression-free survival with D-Rd vs Rd alone. Assessment of pt-reported outcomes alongside efficacy endpoints provides pt perspective on their quality of survival and overall value of HRQoL while on treatments (tx). Methods: The EORTC QLQ-C30 and EQ-5D-5L questionnaires were completed by pts using an electronic device at baseline and every 3 mo during tx; interim results are presented for first 12 mo. Tx effects were assessed using repeated measures, mixed effects models and thresholds for clinically meaningful benefit were based on established criterion from the literature. Results: Compliance rates were high and comparable at baseline ( > 90%) and through month 12 ( > 80%) for both groups (D-Rd [n = 368]; Rd [n = 369]). Improvement in Global Health Status (GHS) occurred in both groups; however, for D-Rd, significantly greater improvement was observed at cycle 3 (LS mean change; D-Rd: 4.5 [95% CI: 2.4, 6.6], Rd: 1.5 [95% CI: -0.7, 3.7]; [p = 0.0454]) and increasing improvement occurred across all time points. Significant improvement and clinically meaningful benefit in HRQoL for D-Rd was also observed in EQ-5D-5L Visual Analog Scale (VAS) scores (LS mean change; D-Rd: 10.1 [95% CI: 8.1, 12.1], Rd: 4.9 [95% CI: 2.8, 7.0]; [p = 0.0002]). The VAS median time to worsening was 10 mo longer for D-Rd. Of note, meaningful differences were observed between the tx groups in two subscale scores, pain symptoms and cognitive functioning. Statistically significant less pain was reported early with D-Rd (LS mean change at cycle 3; D-Rd: -17.9 [95% CI: -20.7, -15.0], Rd: -11.0 [95% CI: -14.0, -8.1]; [p = 0.0007]); clinically meaningful reduction in pain symptoms was sustained with D-Rd. There was a decline in cognitive functioning at cycle 12 in both tx arms, with no statistically significant differences between groups. Conclusions: Faster and sustained improvement in HRQoL was observed in pts treated with D-Rd vs Rd with similar findings reflected across pain subscale. Clinical trial information: NCT02252172.

7526 Background: Stem cell transplant (SCT) was considered to be beneficial in CLL patients with Richter transformation (RT). We report a single center experience of SCT for RT. Methods: CLL patients with biopsy-confirmed RT to DLBCL who underwent SCT were identified from Mayo Clinic CLL database, and clinical information was abstracted by chart review. Survival analysis was done with the Kaplan-Meier method. Results: Twenty-four of 204 RT patients underwent SCT, 20 autologous and 4 allogeneic. The median lines of prior CLL therapy was 1 (range 0-4). Only 4 patients were exposed to ibrutinib prior to RT. The median age at RT diagnosis was 62 (range 41-73). Five of 17 (29%) patients had bulky disease (≥ 5 cm), 12 of 20 (60%) had elevated LDH, and 6 of 15 (40%) had TP53 disruption (del(17p) or TP53 mutation). The median lines of RT therapy prior to SCT was 2 (range 1-4); treatments included R-CHOP-like alone (n = 7), platinum-based alone (n = 1), both R-CHOP-like and platinum-based (n = 11), novel agents (n = 2), and high dose MTX-based (n = 3). Response prior to SCT was CR in 12 (50%) and PR in 12 (50%) patients. The median time from RT diagnosis to SCT was 6.8 months (range 3.3-42.3). After a median follow-up of 52.7 months after SCT, there were 10 RT relapses, 4 CLL progression, and 11 deaths (7 RT, 1 CLL and 3 unrelated). The median progression-free survival (PFS) was 28.5 months (95% CI 8.3-NA; 1-year PFS 61.8%, 2-year PFS 50.5%). The median post-SCT survival was 56.3 months (95% CI 30.6-76.6; 2-year survival 82.0%, 4-year survival 65.6%). Elevated LDH was associated with worse PFS (median 8.9 months vs NA, P= 0.014) and a trend of worse post-SCT survival (53.7 vs 67.4 months, P= 0.153). Other factors including age, prior CLL treatment (untreated vs treated), bulky disease, response prior to SCT, and TP53 disruption were not associated with PFS or post-SCT survival. Among the 4 allogeneic SCT patients, 1 had RT relapse 10.5 months after SCT and was treated with venetoclax, ibrutinib and obinutuzumab and remained alive at last follow-up (12.9 months after SCT). All 3 other patients remained in remission and alive at last follow up (15.6, 16.1 and 108.5 months after SCT, respectively). Conclusions: SCT may benefit select RT patients. The role of SCT in the novel agent era needs further study.

7522 Background: Ibrutinib therapy is associated with an increased risk (~15%) of AF. An accurate risk assessment model for the development of AF in pts starting ibrutinib is not established, and outcomes after AF are not well described. Methods: An IRB approved retrospective review of CLL pts treated with ibrutinib at Mayo Clinic between Oct 2012 and Nov 2018 was conducted. Results: 299 pts were identified with a total of 565 years of ibrutinib exposure (Table). After a median follow-up of 24 months (range 0–70 months), 51 pts developed treatment-emergent AF (13 [25%] CTCAE 3 or higher). Our study assessed 3 clinical prediction models, the Framingham (Schanbel:Lancet 2009), Italian (Visentin:Blood 2018;132:3118), and Shanafelt (Shanafelt:Leuk Lymp; 2017) risk scores. Based on a lower Akaike information criteria, the Italian score was best able to predict risk of treatment emergent AF (2-year risk of AF with score 0 6%; 1-2 8%; 3-4 26%; 5+ 47%). Thirty (61%) pts were treated with medical therapy for AF (27 rate control; 2 rhythm control; 1 both). 16 (31%) pts underwent interventional therapy (3 AV node ablation; 11 cardioversion; and 2 pacemaker). Twelve (23%) pts temporarily held ibrutinib and resumed their original dose, 22 (43%) pts continued reduced dose ibrutinib and 11 (22%) continued their initial ibrutinib dose. Six (12%) pts permanently discontinued ibrutinib. Of 51 pts with treatment-emergent AF, 41 (80%) had a CHA2DS2-VASc score of ≥2 (41% received anticoagulation alone; 12% received antiplatelet therapy alone; 10% received both). No pt developed a thrombotic stroke after treatment-emergent AF. Two major bleeds, (1 GI and 1 intracranial) occurred, one in a pt on concomitant antiplatelet and anticoagulation therapy, and one in a pt receiving neither. The development of AF was associated with shorter event-free survival (HR 2.5, 95%CI 1.5-4.2, p<.001) and shorter overall survival (HR 3.5, 95%CI 2.0-6.3, p<.001). Conclusions: The Italian score was the best predictor of AF development in this cohort of ibrutinib treated pts. Although the vast majority of pts who develop AF after ibrutinib are able to continue therapy, the occurrence of AF appears to be associated with shorter EFS and OS. [Table: see text]

8517 Background: An increased risk of SPM in MM pts treated with len has been reported. We performed an IPD metanalysis to estimate the incidence of SPM according to len exposure. Methods: Randomized studies of MM, from PubMed and ASCO/IMW/ASH (after 2000), that met the following criteria, were included: randomization to treatment with len (len-trials); randomization to treatment including new drug but not len (no-len-trials); available SPM data. Primary aim was to estimate cumulative incidence of SPMs by len exposure, corrected for death (competing event). Results: Data from 6,383 pts (3,218 from 8 len-trials, 3,165 from 10 no-len-trials) were analyzed. Median age was 69 years. During follow-up (median=30 mos) 420 (6.6%) SPMs were reported: 188 (2.9%) hematologic and 232 (3.6%) solid cancers. Solid tumors occurred with similar incidence in all groups. Incidence of hematologic SPM was significantly higher in patients receiving len (3.2 vs 1.1, p=0.04), but risk is limited to patients treated with melphalan+len (4.1, 95%CI: 2.4-5.8) with no excess in other combinations (len without melphalan: 1.2, 0.0-2.6; melphalan without len: 1.1, 0.0-2.7) (p=0.003). The cumulative incidence of death for any cause was much higher than the risk of SPM. Conclusions: The risk of hematologic SPMs was higher in pts receiving melphalan+len. The benefit/risk profile of len treatment remains positive. Cumulative incidence (%) of SPMs and death (95%CI). [Table: see text]