ALBERT

Description: Terrestrial loads of dissolved organic matter (DOM) have increased in recent years in many north temperate lakes. While much of the focus on the “browning” phenomena has been on its consequences for carbon cycling, much less is known about how it influences nutrient loading to lakes. We characterize potential loads of nitrogen and phosphorus to seepage lakes in northern Wisconsin, USA, based on a laboratory soil leaching experiment and a model that includes landscape cover and watershed area. In these seepage lakes, nutrient concentrations are positively correlated with dissolved organic carbon concentrations (nitrogen: r = 0.68, phosphorus: r = 0.54). Using long-term records of browning, we found that dissolved organic matter-associated nutrient loadings may have resulted in substantial increases in nitrogen and phosphorus in seepage lakes and could account for currently observed nutrient concentrations in the lake. “Silent” nutrient loadings to brown-water lakes may lead to future water-quality concerns. ©2018. American Geophysical Union. All Rights Reserved.

Description: Introduction: Approximately 30% of persons with hemophilia A (PwHA) develop neutralizing inhibitors to factor VIII (FVIII) treatment, with peak inhibitor development estimated to occur at 20-50 FVIII exposure days. Emicizumab is a recombinant factor IXa- and factor X-directed antibody, which is Food and Drug Administration approved for prophylaxis in PwHA with inhibitors and is also being evaluated for the treatment of PwHA without inhibitors. We developed a simulation model to estimate the time to inhibitor development in PwHA receiving emicizumab prophylaxis compared with those receiving FVIII prophylaxis. Methods: We developed a decision tree model using Microsoft Excel to estimate the frequency of breakthrough bleeds (BTBs) and development of inhibitors in severe hemophilia A patients over a 20-year period (starting age of patients: 12 months). Patients in the model were assumed to receive either FVIII or emicizumab as prophylaxis. All patients received FVIII for the treatment of BTBs. BTB rates were obtained from HAVEN trials and published sources. Each day of FVIII infusion, regardless of indication (prophylaxis or bleed treatment) was counted as 1 FVIII exposure day. Patients in either treatment arm could develop inhibitors after 20 exposure days, with the probability of developing inhibitors and the number of exposure days required to develop inhibitors assumed to be the same in both arms. However, the risk of inhibitor development was assumed to vary by FVIII treatment i.e. plasma-derived or recombinant. Inhibitors could be transient (resolving spontaneously within 6 months) or persistent. Patients who developed persistent inhibitors could undergo immune tolerance induction (ITI) and, if unsuccessful, switch to prophylaxis and BTB treatment with bypassing agents (BPAs; activated prothrombin complex concentrate [aPCC] for prophylaxis and recombinant activated factor VII [rFVIIa] or aPCC for bleed treatment) in the FVIII arm, and prophylaxis with emicizumab and BTB treatment with BPAs (rFVIIa or aPCC) in the emicizumab arm, without additional ITI attempts. Patients who resolved their inhibitors were assumed not to regain them during the model time horizon. Treatment costs were calculated using drug unit list price (FVIII short acting, emicizumab, rFVIIa and aPCC), dosing was obtained from package inserts and other published sources, and body weight by age was obtained from US growth charts. Key model outcomes included the time to inhibitor development, the total number of BTBs, and total drug costs (in 2018 USD) over the model time horizon. Sensitivity analyses were performed to identify model inputs that were influential on study outcomes, by varying model inputs (±20%). Results: Patients receiving FVIII prophylaxis were estimated to reach 20 FVIII exposure days in 4 months, compared with 162 months in patients receiving emicizumab prophylaxis. The total number of estimated BTBs per patient over 1 year was 1.5 and 5.0; over 5 years, 7.5 and 26.8; and over 20 years, 32.3 and 108.9 in the emicizumab and FVIII arms, respectively. The associated cost savings were estimated at $1.7 million over 20 years for each severe hemophilia A patient initiating emicizumab prophylaxis compared with FVIII prophylaxis. The incremental number of bleeds with FVIII compared with emicizumab prophylaxis was most sensitive to the annual number of BTBs with each prophylaxis regimen; however, results consistently showed fewer bleeds with emicizumab prophylaxis. Conclusions: Assuming the same risk of inhibitor development, emicizumab prophylaxis delayed the development of inhibitors by more than 10 years compared with FVIII prophylaxis. The model suggests that prophylaxis with emicizumab compared with FVIII leads to an avoidance of bleeds and considerable healthcare cost savings. Disclosures Sidonio: Uniqure: Honoraria; CSL Behring: Honoraria; Shire: Honoraria, Research Funding; Genentech/Roche: Honoraria, Research Funding; Kedrion/Grifols: Research Funding; Bioverativ: Honoraria, Research Funding; Biomarin: Honoraria; Novo Nordisk: Honoraria. Patel:Genentech Inc: Employment. Corman:Genentech, Inc.: Consultancy. Raimundo:Genentech Inc: Employment, Other: Ownership interests PLC.

Description: INTRODUCTION Peripheral T cell lymphomas (PTCL) are a rare and heterogenous group of aggressive non-Hodgkin lymphomas (NHL) that develop from mature T- and natural killer cells. They comprise approximately 10% of all newly diagnosed cases of NHL in Western populations. The current study characterizes real-world treatment patterns and outcomes among patients with PTCL in France and the United Kingdom (UK) in the first-line (1L) setting. METHODS A retrospective medical chart review study was undertaken at geographically disparate clinical sites in France and UK, where treating physicians were responsible for patient selection and data collection via structured case report forms. Adults (≥18 years) with newly diagnosed with PTCL between January 1, 2014 and December 31, 2016 were randomly selected for inclusion in the study. Eligible patients had received at least 1L treatment (1LT) for PTCL and had available clinical data for ≥1 year after PTCL diagnosis or until death. Patients enrolled in a clinical trial for 1L PTCL at any time between diagnosis and end of follow-up or who had any prior unresolved malignancy within 5 years of PTCL diagnosis were excluded. Demographic, clinical, and immunophenotypic/cytogenetic profiles of PTCL patients were assessed at diagnosis. Treatments received and best response as reported by the treating clinician (categorized as complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]) at the end of 1LT are described. Data from both countries were pooled for the current analysis. RESULTS Overall, 32 haematologist/oncologists (France, 15; UK, 17) with a median of 12.5 years of clinical practice participated in the study. Most physicians in France practiced at a university hospital or a regional hospital centre (73.3%). In the UK, most physicians practiced at a specialist cancer/ tertiary referral treatment centre (47.1%). A total of 109 patients (France, 53; UK, 56) received at least 1L PTCL treatment during the study period. The median age at diagnosis was 63 years (range, 19 to 84 years), with a male predominance (57.8%). Eighty percent of patients had an ECOG performance status of 0-1 at diagnosis. B symptoms were present in 59.6% and extranodal disease was present in 35.8% patients at diagnosis. Most patients (72.5%) had stage III or IV disease and (64 of 102) 62.75% were classified as intermediate risk (score of 2-3) as per the International Prognostic Index. The most common histological subtypes were PTCL-not otherwise specified (NOS) (37.6%), angioimmunoblastic T-cell lymphoma (29.4%), and systemic anaplastic large cell lymphoma (20.2%). The median duration of follow-up was 34 months from the start of 1L PTCL treatment. Of those tested, 60.4% patients were positive for CD30 (information on threshold was not reported). Only 19.3% patients underwent testing for any cytogenetic marker. During follow-up, 28.4% of patients had died. In the 1L setting, 59.6% and 26.6% patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and with CHOEP/CHOEP‐like regimens (Table). Median duration of 1LT was 4.9 months. Stem cell transplant was undertaken in 29.4% patients as part of 1L treatment, of which 84.4% were autologous. PET-CT was used for response assessment in 56% of patients. Best response within 1 year of completing 1LT and before start of 2L treatment was assessed in 75/109 [68.8%] patients (Table); of whom 80% (60 patients) were reported to have a complete response (Table), and about 39% relapsed (within the first year) and went on to 2L treatment. The remaining 27 patients had best response assessed prior to completion of 1LT. Brentuximab vedotin (19%) and GemOx (19%) were the most common 2L treatments. CONCLUSIONS This retrospective observational study describes treatment patterns and key clinical outcomes among patients receiving 1L PTCL treatment in France and the UK. CHOP-based regimens were used to treat 59.6% of the study patients. Understanding distribution of PTCL subtypes and outcomes of treatment in routine clinical practice is complementary to data derived from clinical trials and crucial to facilitate improvement of survival outcomes through the introduction of novel therapies for this challenging group of rare malignancies. Disclosures Fox: Janssen: Consultancy; Adienne: Other: Travel Support; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Sunesis: Consultancy. Ashaye:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Shah:Pfizer: Research Funding; Merck: Research Funding; Bayer: Research Funding. Dalal:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Truemper:Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Roche: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding.

Description: Introduction: By now, the pandemic spread of COVID-19 (coronavirus disease 2019) has claimed more than 600,000 lives. The adaptive immune response seems to play a major role in the progression of the disease, since entry of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is determined by a spike protein recognized by T helper cells. This has been linked to the clinical finding of severe lymphocytopenia in these patients. However, detailed cellular immune responses in the bone marrow (BM) and in the spleen (SPL) of COVID-19 patients have not been addressed yet. Here, we provide novel immunologic insight with potential for therapeutic management and risk stratification in COVID-19. Material and Methods: We performed complete autopsies on 11 confirmed COVID-19 and 4 non-COVID-19 deceased, who were matched for risk profile and age. SARS-CoV-2 load was measured by rt-PCR (quantitative real-time polymerase chain reaction) targeting the SARS-CoV-2 E-gene in purified RNA extracts from 50mg of pulmonary tissue (MagNAPure 96 system, Viral NA Large Volume Kit, Roche). For histopathology, representative tissue samples of decalcified BM and SPL were fixed in 4 % buffered formalin, dehydrated and paraffin embedded. Sections were stained with HE, PAS, Giemsa-, Gomori- and Prussian blue stain. Furthermore, BM and SPL were stained with immunohistochemical reagents, namely MPO (Myeloperoxidase), CD235, CD34, CD117, CD68, CD61, CD20, CD3, CD4, CD8, CD138, HLA-DR (Human Leucocyte antigen - DR isotype), PD-1, PD-L1 (Programmed cell death protein and ligand 1), Ki67 and Caspase3 (Ventana Ultra and LEICA Bond III). Additionally, we performed in-situ hybridization of EBV (Epstein-Barr-Virus; LEICA Bond MAX), followed by PCR of the EBV nuclear antigen 1 (Thermo Fisher and Roche). Histopathology was evaluated by at least two hematopathologists. Clinical data were obtained from patients' files. Statistical analysis was done using GraphPad Prism8 Software. Inc, 2018. Results: Of all COVID-19 deceased, 73% (n = 8/11) showed BM hypercellularity, increased granulocyte / erythrocyte ratios, and left shift of erythro- and granulopoiesis with anemia and an increase of immature granulocytes in the peripheral blood. Thromboembolic events were present in 82% (n = 9/11) of COVID-19 patients and related to an increase and left shift of megakaryopoiesis in the BM. In the BM of patients with severe bacterial superinfection of COVID-19 pneumonia, we observed an early increase of PD-L1 expression on myeloid cells, lymphocytic apoptosis, and time-dependent macrophage anergy with a continuous loss of antigen-presenting capacity. Furthermore, we found CD20+ B-cell depletion in either BM or SPL in 64% (n = 7/11) of COVID-19 patients with B-cell counts of less than 1% in the BM and 1-5% in the SPL, followed by complete plasma cell depletion. This was reflected by severe lymphocytopenia in the peripheral blood. In contrast, BM T-cell counts were nearly as high in COVID-19 decedents (median 10%) as in cases not related to COVID-19 (median 12.5%). Interestingly, there was a tendency towards higher pulmonary SARS-CoV-2 RNA load in COVID-19 patients with B-cell depletion, as we observed maximum viral copy numbers of up to 1,150,000 / 10,000 cells in patients with B-cell depletion as compared to 6,500 / 10,000 cells in patients with B-cell preservation. EBV was absent in all cases. Clinical characteristics and time-intervals between initial symptoms and death of COVID-19 patients were heterogenous, therefore preventing the detection of a clinical risk profile in patients with B-cell depletion. Conclusion: Our results show that severe lymphocyte depletion in COVID-19 deceased is caused by a substantial loss of B-cells which is in turn associated with viral SARS-CoV-2 burden and presumably results from excessive activation of the adaptive immune system. It is yet to be determined how B-cell specific pathways are affected by SARS-CoV-2 and whether this might serve as a therapeutic target of interest. Moreover, we provide morphologic evidence, that COVID-19 pneumonia with bacterial superinfection is aggravated by sepsis acquired immunodeficiency. Since the latter is associated with an epigenetically determined switch to endotoxin tolerance, our findings may additionally aid in risk stratification of COVID-19 patients who undergo severe bacterial superinfection during the disease. Disclosures Bullinger: Menarini: Membership on an entity's Board of Directors or advisory committees; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Non-persistence to treatment with hypomethylating agents (HMA) in higher-risk myelodysplastic syndrome (HR-MDS) patients can result in loss of response or ability to achieve a primary response. HMA treatment is recommended to be given to HR-MDS patients for least 4-6 treatment cycles to elicit a clinical response and premature termination is likely to result in poor outcomes and considerable healthcare spending. The study objective was to assess direct medical costs associated with HMA treatment non-persistence among HR-MDS patients. Methods: Using a retrospective cohort design, MDS patients with refractory anemia with excess blasts (RAEB) were analyzed using 2010-2016 Surveillance, Epidemiology and End Results-Medicare linked database. RAEB diagnosis is considered to substantially overlap with HR-MDS and has been used as a surrogate for HR-MDS. The study cohort included RAEB patients diagnosed between 01/2011 and 12/2015. Patients were included if they had ≥ 1 year of continuous Medicare enrollment prior to diagnosis and did not receive stem cell transplant or lenalidomide in the follow-up period. HR-MDS patients receiving HMAs were stratified into HMA persistent (receiving 4 or more HMA cycles without any gap of ≥90 days between cycles) and HMA non-persistent (receiving less than 4 cycles or a gap of ≥90 days between cycles) groups. Healthcare resource use (HCRU) and associated direct medical costs incurred during the follow-up period were described as per-patient-per-month (PPPM). To account for baseline differences between HMA persistent and non-persistent groups, propensity score-based inverse probability of treatment weights (IPTW) were calculated. Weighted HCRU and costs (PPPM) were further estimated using generalized linear models (GLMs). Costs were inflated to 2019 USD using medical component of consumer price index. Results: There were 664 patients identified with RAEB, of which 295 (44.4%) patients were classified in the HMA non-persistent group and 369 (55.6%) patients in the HMA persistent group. HMA persistent and non-persistent groups were similar in baseline demographic and clinical characteristics; however, non-persistent HMA users were older at diagnosis and a lower proportion of patients were married. Results from weighted GLM analysis indicated higher PPPM resource utilization in HMA non-persistent patients compared to HMA persistent patients specifically for hospitalizations (Incident rate ratio [IRR], 1.543, 95% Confidence interval [CI]: 1.181 - 2.018]), ER visits (IRR= 1.322, 95% CI: 1.146 - 1.524), SNF use (IRR = 2.158, 95% CI: 1.308 - 3.560), home health (IRR = 1.335, 95% CI: 1.039 - 1.714] and hospice care use (IRR = 2.555, 95% CI:1.972 - 3.309) (Table 1). Further, HMA non-persistent patients had significantly (P