bluuebunny/crossref_metadata_2025 huggingface dataset:
Documenting rubble to shift baselines: Environmental assessments and damaged glaciers in Chile
Authors: Barandiarán Javiera
Published: November 2019

Worldwide, governments use environmental impact assessments (EIAs) to manage the environmental impacts of industrial activity. EIAs contain baselines that describe the specific environment where the project would go, and impact evaluations that identify ways to eliminate, reduce, or compensate the environmental harms the project would have. Although EIA baselines promised to democratize and improve decision-making, in practice, many affected communities, environmental activists, and scholars of EIAs find that baselines often obscure certain ecological impacts. Drawing on science and technology studies and environmental history, I reflect on why this happens and propose that it results from the ways in which EIA baselines reproduce modernist views of economic growth and progress. I analyze EIA baselines as a “memory practice” which meet the needs of the present by projecting a timeless, static past to be preserved. This naturalization of modernism can be challenged through two correctives: to compare projects rather than natures in EIA baselines, and to document existing and potential forms of “rubble” resulting from industrial activity. I illustrate these arguments with the case of glaciers and efforts to protect them from the impacts of the Pascua Lama gold mine located in the high-altitude Andes.
Nano-finishing of MEMS-based platforms for optimum optical sensing
Authors: Gupta Ankur , Sundriyal Poonam , Basu Aviru , Manoharan Kapil , Kant Rishi , Bhattacharya Shantanu
Published: November 2019

The surface finish of the microelectromechanical systems substrate, particularly the ones that are deployed in chip-based optofluidic systems, is of utmost importance, and the overall surface finish helps in preventing light scattering and associated losses. The proposed system is made up of a microchannel with a coating on its interior which acts as a cladding layer and possesses an air-like refractive index. The water-based solutions with refractive indices higher than the coating, when confined within such channels, act as waveguides with a refractive index difference which would allow grazing incidence at the solution film interface. The microchannel is fabricated over a piece of Si along <100> direction with the help of lithography and wet etching technique. After wet chemical etching of silicon, multiple pyramidal hillocks with overall large surface roughness is observed which are not appropriate for loss-free light transmission and cause various optical losses. So the overall optimization of surface roughness created by the etching processes is critical from an optical standpoint. Roughness in the microchannel surface mainly arises due to wet etching through tetra methyl alcohol, potassium hydroxide, potassium ferricyanide and isopropyl alcohol. In this work, we have obtained surface finish upto ~1.33 nm at an etch rate of 141 nm/min which is obtained by tweaking the composition of the participating reagents in the etchants and also the etching temperature. The surface roughness obtained is quite small in comparison to the wavelength range of the visible spectrum and thus losses were greatly avoided. The low refractive index films over silicon substrate were characterized by field emission scanning electron microscopy, energy dispersive analysis of X-ray, atomic force microscopy, 3D optical profilometry and ellipsometry. The transmission results show that transmission loss was reduced by 27.42% for the coated samples with 33 nm surface roughness as compared to surface with 250 nm roughness.
Autophagy in the Hematopoietic System
Authors: Simon Anna K. , Obba Sandrine , Zhang Hanlin , Riffelmacher Thomas
Published: November 2019

Autophagy, the major lysosomal degradation pathway in the cell plays a key role in the maintenance of metabolism, healthy mitochondria and limits reactive oxygen species, thus keeping the genome and proteome healthy. We demonstrated that erythroblasts rely on mitophagy as they differentiate into erythrocytes 1 and that hematopoietic stem cells (HSCs) require autophagy to survive and repopulate a new hematopoietic system 2. Genetic ablation of Atg7 in the hematopoietic system, which encodes a component of the autophagy system, resulted in a pre-leukemic phenotype, which predicted low autophagic flux found in blasts from patients with acute myeloid leukemia 3. Most recently, our studies indicate that autophagy provides free fatty acids for neutrophil differentiation by degrading lipid droplets 4. However, it is not clear what is degraded by autophagy in HSCs or whether autophagy is required to provide building blocks to the HSC and what the nature of these building blocks is. We are currently addressing this by using state-of-the-art in vivo techniques, and I will report our findings in my presentation.

1 Mortensen, M., Ferguson, D. J., Edelmann, M., Kessler, B., Morten, K. J., Komatsu, M. & Simon, A. K. Loss of autophagy in erythroid cells leads to defective removal of mitochondria and severe anemia in vivo. Proc Natl Acad Sci U S A 107, 832-837, doi:10.1073/pnas.0913170107 (2010).

2 Mortensen, M., Soilleux, E. J., Djordjevic, G., Tripp, R., Lutteropp, M., Sadighi-Akha, E., Stranks, A. J., Glanville, J., Knight, S., Jacobsen, S. E., Kranc, K. R. & Simon, A. K. The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance. J Exp Med 208, 455-467, doi:10.1084/jem.20101145 (2011).

3 Watson, A. S., Riffelmacher, T., Stranks, A., Williams, O., De Boer, J., Cain, K., MacFarlane, M., McGouran, J., Kessler, B., Khandwala, S., Chowdhury, O., Puleston, D., Phadwal, K., Mortensen, M., Ferguson, D., Soilleux, E., Woll, P., Jacobsen, S. E. & Simon, A. K. Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia. Cell Death Discov 1, doi:10.1038/cddiscovery.2015.8 (2015).

4 Riffelmacher, T., Clarke, A., Richter, F. C., Stranks, A., Pandey, S., Danielli, S., Hublitz, P., Yu, Z. R., Johnson, E., Schwerd, T., McCullagh, J., Uhlig, H., Jacobsen, S. E. W. & Simon, A. K. Autophagy-Dependent Generation of Free Fatty Acids Is Critical for Normal Neutrophil Differentiation. Immunity 47, 466-480, doi:10.1016/j.immuni.2017.08.005 (2017).

Disclosures

No relevant conflicts of interest to declare.
Histone Modifications in Development and Malignancy
Authors: Oricchio Elisa
Published: November 2019

Non-Hodgkin lymphoma (NHL) development is driven by the accumulations of multiple genetic, epigenetic, and chromosomal alterations. These lesions can lead to modifications of the chromatin architecture. To identify novel oncogenic interactions driven by modifications of the chromatin 3D organization, we combined high-throughput chromatin conformation capture data (Hi-C) in lymphoma cells with whole genome sequencing (WGS) and epigenetic and transcriptional profiles of primary patient samples and cell lines. Recently, we found that a significant interplay exists between the compartmentalization of the genome into topologically associating domains (TADs) and epigenetic and transcriptional changes mediated by mutated EZH2. Indeed, EZH2 mutations drive aberrant increase of H3K27me3 within specific TADs, resulting in loss of promoter-promoter interactions, synergistic silencing of multiple tumor suppressors and, thus, increased B-cell proliferation and tumor aggressiveness1. Now, we are further investigating how chromosomal amplifications and translocations forms new long-range interactions between enhancers and promoters to support oncogene expression. Importantly, we observed that epigenetic editing of enhancers and pharmacological depletion of H3K27Ac reduces the number of interactions between specific enhancers and promoters and this loss of interactions directly affects gene expression and cell differentiation. These results indicate that is possible to block the oncogenic effect of chromosomal alterations by targeting epigenetic modification in enhancer regions and preventing the formation of oncogenic chromatin interactions. Overall, our results demonstrate that it is important to contextualize the effects of genomic alterations in the 3D organization of the chromatin, to uncover new oncogenic mechanisms and improve the design of new therapeutic approaches.

Donaldson-Collier MC, Sungalee S, Zufferey M, et al. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nat Genet. 2019;51(3):517. doi:10.1038/s41588-018-0338-y

Disclosures

No relevant conflicts of interest to declare.
Cutaneous Hemorrhage Types As Supportive Factors for Predicting Chronic Immune Thrombocytopenia in Children
Authors: Sharon Nehama
Published: November 2019

Our objective was to assess risk factors for developing chronic immune thrombocytopenia (ITP) in children. The charts of all consecutive children diagnosed with ITP between 2000 and 2015 at a single center were retrospectively reviewed, and clinical characteristics at initial presentation were analyzed. Sixty-two children were included in the study (mean age, 6.15 y); 44 (71%) were found to have acute ITP, and 18 (29%) developed chronic ITP (permanent or relapsing thrombocytopenia >12 mo). In a univariate analysis, cutaneous hemorrhages were observed significantly more in acute patients (90.9%) than in chronic patients (61.1%). Patients who had acute ITP were more likely to present with a combination of petechiae, purpura, and/or ecchymosis (75%) than patients with chronic disease (44.4%, P=0.010). In multivariate analysis, older age increased the risk (odds ratio=1.1; P<0.05) for chronic disease, and manifestations of combination skin hemorrhages (petechiae/purpura/ecchymosis) reduced the risk (odds ratio=0.167; P<0.05). In conclusion, the most important risk factor for chronic disease is older age. Skin hemorrhage types were found to be a supportive factor for the prediction process: the combination of petechia/purpura/ecchymosis was associated with a lower risk for developing chronic disease compared with petechiae alone. Future studies should assess the prognostic value of skin hemorrhage types that are a simple way to predict the course of ITP in children.

Disclosures

No relevant conflicts of interest to declare.
Preclinical Evaluation of CD8+ Anti-Bcma mRNA CAR T-Cells for the Control of Human Multiple Myeloma
Authors: Lin Liang , Xing Lijie , Cho Shih-Feng , Wen Kenneth , Hsieh Phillip A , Kurtoglu Metin , Zhang Yi , Stewart C Andrew , Anderson Kenneth C. , Tai Yu-Tzu
Published: November 2019

Chimeric antigen receptor (CAR) T cells targeting BCMA are positioned to transform treatment of multiple myeloma (MM), and virally-generated anti-BCMA CAR T cells have shown impressive early stage clinical results. However, the safety risk/benefit, manufacturing constraints, and relevant patient populations of viral anti-BCMA CAR T have yet to be fully defined. Here we present preclinical characterization of an autologous mRNA-generated anti-BCMA CAR T cell product (Descartes-08) designed to reduce safety risk and broaden the fitness-for-use of anti-BCMA CAR T cell therapy. Descartes-08 are autologous CD8+ T cells that express anti-BCMA CAR on up to 90% of cells with duration of CAR expression for several days with subsequent reduction in expression to background approximately 1 week after their generation. The manufacturing process is clinically scalable with high purity and viability of Descartes-08 following cryopreservation. Descartes-08 undergo cytotoxic degranulation and produce cytokines IFNg, TNFα, IL-2, in response to multiple BCMA-expressing multiple myeloma target cell lines in an effector-to-target-ratio-dependent manner. Furthermore, Descartes-08 kills MM lines that are both resistant and sensitive to lenalidomide and pomalidomide, and/or MM cells that are grown in the presence of bone marrow stromal cells that clinically support MM survival. Moreover, Descartes-08 are highly cytotoxic against MM cells from both newly-diagnosed and relapsed patients. The magnitude of cytolytic and cytokine responses correlates with duration of anti-BCMA CAR expression and declines after 4 days, indicating a temporal limit in activity that is predicted to dramatically decrease the risk of severe cytokine release syndrome. In a mouse model of disseminated human MM, Descartes-08 shows CAR-specific suppression of myeloma that is maintained throughout the duration of treatment. Taken together, these results illustrate features of RNA-generated anti-BCMA CAR T cells that promise key clinical advantages, thereby supporting ongoing clinical development of Descartes-08 for treatment of MM (NCT03448978).

Disclosures

Kurtoglu: Cartesian Therapeutics: Employment. Zhang:Cartesian Therapeutics: Employment. Stewart:Cartesian Therapeutics: Employment. Anderson:Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder ; Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board.
Clinical Utility of B- and T-Cell Gene Rearrangement Studies in Blood and Bone Marrow Samples
Authors: Mendoza Hadrian , Tormey Christopher , Siddon Alexa J.
Published: November 2019

In the evaluation of bone marrow (BM) and peripheral blood (PB) for hematologic malignancy, positive immunoglobulin heavy chain (IG) or T-cell receptor (TCR) gene rearrangement results may be detected despite unrevealing results from morphologic, flow cytometric, immunohistochemical (IHC), and/or cytogenetic studies. The significance of positive rearrangement studies in the context of otherwise normal ancillary findings is unknown, and as such, we hypothesized that gene rearrangement studies may be predictive of an emerging B- or T-cell clone in the absence of other abnormal laboratory tests. Data from all patients who underwent IG or TCR gene rearrangement testing at the authors' affiliated VA Hospital between January 1, 2013 and July 6, 2018 were extracted from the electronic medical record. Date of testing; specimen source; and morphologic, flow cytometric, IHC, and cytogenetic characterization of the tissue source were recorded from pathology reports. Gene rearrangement results were categorized as true positive, false positive, false negative, or true negative. Lastly, patient records were reviewed for subsequent diagnosis of hematologic malignancy in patients with positive gene rearrangement results with negative ancillary testing. A total of 136 patients, who had 203 gene rearrangement studies (50 PB and 153 BM), were analyzed. In TCR studies, there were 2 false positives and 1 false negative in 47 PB assays, as well as 7 false positives and 1 false negative in 54 BM assays. Regarding IG studies, 3 false positives and 12 false negatives in 99 BM studies were identified. Sensitivity and specificity, respectively, were calculated for PB TCR studies (94% and 93%), BM IG studies (71% and 95%), and BM TCR studies (92% and 83%). Analysis of PB IG gene rearrangement studies was not performed due to the small number of tests (3; all true negative). None of the 12 patients with false positive IG/TCR gene rearrangement studies later developed a lymphoproliferative disorder, although two patients were later diagnosed with acute myeloid leukemia. Of the 14 false negatives, 10 (71%) were related to a diagnosis of plasma cell neoplasms. Results from the present study suggest that positive IG/TCR gene rearrangement studies are not predictive of lymphoproliferative disorders in the context of otherwise negative BM or PB findings. As such, when faced with equivocal pathology reports, clinicians can be practically advised that isolated positive IG/TCR gene rearrangement results may not indicate the need for closer surveillance.

Disclosures

No relevant conflicts of interest to declare.
Hyperphosphatemia Contributes to Inflammation and Iron Dysregulation in Models of Normal and Impaired Renal Function
Authors: Czaya Brian , Richter Beatrice , Yanucil Christopher , Campos Isaac , Heitman Kylie , Faul Christian
Published: November 2019

Background

Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that targets the kidney to promote urinary phosphate excretion. In patients with chronic kidney disease (CKD), serum concentrations of phosphate (Pi) and FGF23 gradually increase as renal function declines and associate with various pathologies, including systemic inflammation and anemia. Our previous studies revealed FGF23 contributes to inflammation by directly targeting hepatocytes via FGF receptor 4 (FGFR4) and inducing phospholipase Cγ (PLCγ) signaling and the expression of inflammatory cytokines. Experimental studies have shown Pi can accelerate CKD-associated pathologies, but direct effects of Pi on the liver are not well described. Here we compare the effects of Pi versus FGF23 on hepatocytes and determine their respective contributions to inflammation and anemia in the context of CKD.

Methods

We subject mice with global deletion of FGFR4 and wild-type littermates to increasing dietary Pi load (0.7%, 2.0%, or 3.0%) or an adenine-rich diet (used as a CKD model) in order to examine systemic inflammation and alterations in iron metabolism in the setting of normal and impaired renal function. In addition, we study primary mouse hepatocytes treated with FGF23 and increasing Pi concentrations and examine the activation of downstream signaling events and expression levels of specific target genes. Furthermore, we determine if co-treatment with inhibitors of Pi uptake and downstream signal mediators block the observed effects.

Results

A 3% Pi diet as well as an adenine-rich diet promote inflammation and iron dysregulation in mice. These effects are exacerbated in FGFR4 knockout mice. In cultured hepatocytes, expression of inflammatory cytokines, hepcidin and FGF23 are induced by Pi in a dose-dependent manner. Furthermore, Pi activates NFkB signaling and the inhibition of Pi uptake and of NFkB protects from Pi-induced effects.

Conclusion

We postulate that in CKD, gradual elevations in serum Pi promote inflammation and anemia by targeting the liver to induce gene programs which regulate the inflammatory response and iron metabolism. Our study indicates these Pi effects may be independent of FGF23. Pharmacological approaches targeting hyperphosphatemia or hepatic Pi actions might alleviate various CKD-associated pathologies.

Disclosures

No relevant conflicts of interest to declare.
Molecular Alterations in Adult Histiocytic Neoplasms
Authors: Goyal Gaurav , Abeykoon Jithma P. , Bennani Nora N , Liu Minetta C , Shah Mithun Vinod , Go Ronald S.
Published: November 2019

Introduction

Histiocytic neoplasms are rare disorders of the monocyte-macrophage-dendritic cell lineage that pose significant management challenges to the clinicians. Over the last five years, there has been emerging data on the role of MAPK/ERK pathway (RAS-RAF-MEK-ERK) in their pathogenesis. In this study, we report the molecular alterations among patients with histiocytic neoplasms seen at our institution.

Methods

We pursued target-capture next generation sequencing (NGS) on tissue specimen of patients with various histiocytic neoplasms- Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), Rosai-Dorfman disease (RDD), histiocytic sarcoma (HS), and Langerhans cell sarcoma (LCS). We used three NGS platforms, Tempus® xO (1,714 genes), Tempus® xT (596 genes), or Foundation One® CDX (324 genes). All platforms used formalin-fixed paraffin-embedded tumor tissue specimens for detection of substitutions, insertion and deletion alterations, and copy number alterations, and gene rearrangements. The Tempus assays also utilized matched blood or saliva samples for germline DNA sequencing in addition to whole-transcriptome RNA sequencing. The tumor cellularity threshold for pursuing RNA sequencing was 30% so the test was not pursued specimens for lower cellularity.

Results

We included 31 cases with histiocytic neoplasms in this study. The disease distribution was as follows: ECD (n=6), LCH (n=7), RDD (n=12), ECD-RDD overlap (n=3), HS (n=2), and LCS (n=1). Among the 13 patients with ECD and LCH, BRAF-V600E mutations were found in 8 (62%) cases. We found several novel DNA alterations in this study in all disease groups: ECD (BRAFV471F), LCH (MAP2K1 in-frame deletion), and RDD (frameshift mutations of DNMT3A, SMARCA4, KMT2A, and CDC73 truncation). In one LCH patient without any DNA alterations, we found MAPK1 and MAP2K1 overexpression on RNA sequencing. We also had two cases with HS, both of which were found to have KRAS exon 3 mutations. One of these cases had concomitant JAK2V617F+ myelofibrosis and the tissue specimen for HS demonstrated TET2 and SRSF2 mutations as well. Our cohort included one patient with multifocal lymph node LCS that demonstrated NRAS and TP53 mutations, who did not respond to MEK-inhibitor therapy. Alterations in epigenetic regulators (TET2, DMNT3A, KMT2A, ASXL1) were found in 5 (16%), potentially suggesting clonal hematopoiesis in a subgroup of histiocytosis.

Conclusions

Histiocytic neoplasms demonstrate diverse somatic oncogenic alterations. In our study, we noted several novel alterations beyond the MAPK-ERK pathway in RDD that may point toward other potentially pathogenic mechanisms for these rare disorders. In cases where the DNA sequencing does not reveal pathogenic alterations, transcriptome analysis may aid in the diagnosis and management.

OffLabel Disclosure:

Trametinib use for Langerhans cell sarcoma
A Novel and Potent EZH1/2 Dual Inhibitor HM97594 for the Treatment of Hematological Malignancies
Authors: Jung Seung Hyun , Hong DongJin , Kim SeoHee , Hwang Jiyoung , Byun Jooyun , Lee Miyoung , Koo Kyounghwa , Lee Gunwoo , Song TaeHun , Lim SunYoung , Kim Yu-Yon , Park Hyunjin , Bak Yesol , Ko Myoungsil , Jung Sunyoung , Han Yuri , Ahn YoungGil , Kim YoungHoon , Suh KweeHyun
Published: November 2019

In mammals, either enhancer of zeste homologue 2 (EZH2) or its homolog EZH1 functions as the catalytic subunit of polycomb repressive complex 2 (PRC2), and plays an essential role for the maintenance of transcriptional repression by the trimethylation of histone H3 lysine 27 (H3K27me3). Hyperinduction of H3K27me3 mediated by EZH2 overexpression or EZH2 gain-of-function (GOF) mutation (e.g. Y641, A677 and A687) has been associated with lymphoma and myeloma progression. Many publications suggest that suppressing PRC2 activity by EZH2 inhibition is a potential therapeutic target for hematological malignancies. Up to date, there are known a few EZH2 selective inhibitors with showing anti-tumor activity in some preclinical and clinical studies.

However, the inhibition of EZH2 can complementarily induce EZH1 activation, which reactivates PRC2 function in turn. Therefore, dual inhibition of EZH1 and EZH2 could give more effective than EZH2 inhibition alone in blocking PRC2 function as an anti-cancer therapy. Herein, we introduce a novel EZH1/2 dual inhibitor, HM97594, which simultaneously inhibits the methyltransferase activity of wild-type EZH1 as well as wild-type and GOF mutant EZH2 at nanomolar concentrations.

HM97594 potently repressed trimethylation of H3K27 in lymphoma and myeloma cell lines. As a result, HM97594 showed broader and stronger activities than EZH2 selective inhibitors in in vitro studies of inhibiting the proliferation of various hematological cancer cell lines. HM97594 induced the differentiation of DLBCL to plasma cells with an increment of cell lineage specific markers (e.g. PRDM1, IRF4 and CD38) and decreased the colony forming ability. Also, HM97594 caused cell cycle G0/1 arrest and apoptosis in KARPAS-422 cells harboring EZH2 Y641 GOF mutation.

In addition, HM97594 showed potent antitumor activity in KARPAS-422 lymphoma cell xenograft mouse model. Once daily orally administered HM97594 greatly inhibited tumor growth in a dose-dependent manner without body weight loss compared to the known EZH2 inhibitor.

Collectively, it was demonstrated in the present studies that HM97594, EZH1/2 dual inhibitor, has promising potential as an anticancer drug for patients with subtypes of hematological malignancies. Further preclinical studies will be performed and reported soon after the establishment of a preclinical candidate.

Disclosures

No relevant conflicts of interest to declare.
Retrospective Electronic Medical Records Study of Treatment Patterns Among CLL Patients in the CancerLinQ Research Database
Authors: Kabadi Shaum M , Kumar Supriya R , Wong Jennifer L
Published: November 2019

Background: Chronic lymphocytic leukemia treatment has changed dramatically with the emergence of novel targeted therapies. Data generated on CLL treatments are mostly from clinical trials, which are primarily conducted at academic centers. There are limited data on contemporary CLL treatment patterns in the community practice setting in the United States (US).

Methods: Adults with CLL who initiated treatment between November 1, 2013 and March 31, 2018 were identified retrospectively from electronic health records (EHR) from the CancerLinQ Discovery Research Database and followed up until March 31, 2019. A random sample of patients were selected for further study. Patients enrolled in clinical trials or who had another primary cancer diagnosis within 2 years of CLL treatment start were excluded. Index date was record of first treatment for CLL. Baseline demographics, comorbidities, and treatment characteristics were derived from structured data elements of the EHR or abstracted from clinical notes in the EHR.

Results: 338 patients with a median follow-up of 26.9 months (range, 0.5-63.8), were included. Median age at treatment initiation was 69.7 years; 57.1% were male (Table 1). Of patients (n=110) with a known Eastern Cooperative Oncology Group (ECOG) score at diagnosis, 53.6% and 35.5% had an ECOG performance status of 0 and 1, respectively. The 3 most common treatments used for CLL regardless of line of therapy were rituximab (63.9%), ibrutinib (36.4%), and bendamustine (34.0%). Furthermore, the 3 most common comorbidities at index were hypertension (19.2%), anemia (16.0%), and thrombocytopenia (5.6%).

Conclusions: This is the first published real-world observational study in CLL using the CancerLinQ Discovery Research Database, providing information on baseline characteristics of patients with CLL receiving treatment in the community setting in the US. Additional analyses evaluating treatment-related adverse events and associated outcomes for CLL-directed treatments by line of therapy are ongoing.

Disclosures

Kabadi: AstraZeneca: Employment, Equity Ownership. Kumar:AstraZeneca: Employment, Equity Ownership. Wong:AstraZeneca: Employment, Equity Ownership.
Change in Treatments and Complications after Regionalizing High-Intensity Induction of Acute Myeloid Leukemia in a Community-Based Population, 2013-2017
Authors: Law Lisa Y , Uong Stephen , Ho Gwendolyn , Vempaty Hyma T. , Baer David M. , Liu Vincent , Herrinton Lisa
Published: November 2019

Introduction: Patients with acute myeloid leukemia (AML) may receive more appropriate care when treated regionally instead of locally, but studies have not adequately accounted for baseline differences between regional and local cohorts. In 2015, Kaiser Permanente Northern California, an integrated healthcare delivery system, started to shift AML induction from local (N=21) to regional (N=3) centers. We assessed the association of regionalization with the frequency of use of induction therapy and bone marrow transplantation, and with 60-day mortality.

Methods: Information for all adult health plan members with ≥1 year of enrollment before receiving a diagnosis of AML during 2013-17 was obtained from the electronic health record. Multivariable methods were used to compare risk of induction, bone marrow transplantation, and death before and after 2015 (i.e., 2013-14 and 2016-17) after adjustment for baseline characteristics.

Results: Of 662 patients, 38% were ≥75 years, 30% had an Elixhauser comorbidity index ≥5, and 10% died within the week following diagnosis. Among non-APL patients, we observed increased use of induction therapy (65% vs 49%, p=0.0003) and bone marrow transplantation (23% vs 13%, p=0.007) after 2015, while the 60-day mortality rate did not change (before 2015, 94 of 278 [32.7%]; after 2015, 82 of 249 [32.9%]; p=0.83).

Conclusion: In this community-based population that includes advanced elderly patients with substantial comorbidity, regionalization was associated with increased use of induction therapy and bone marrow transplantation but no increase in the risk of 60-day mortality. Older patients can benefit from AML induction therapy at specialized centers.

Figure

Disclosures

No relevant conflicts of interest to declare.
Myeloablative Conditioning Is Preferred for Allogeneic Transplantation of Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate but Not High Disease Risk Index
Authors: Bejanyan Nelli , Zhang Mei-Jie , Bo-Subait Khalid , Wang Hai-Lin , Warlick Erica D. , Brunstein Claudio G , Sandmaier Brenda M , Litzow Mark , Kebriaei Partow , Saber Wael , Weisdorf Daniel J.
Published: November 2019

Although some data (Scott, JCO 2017) suggest that myeloablative conditioning (MAC) is preferred for allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), these data were not informed by analysis of disease specific risk factors. We analyzed AML and MDS HCT outcomes stratified by the disease risk index (DRI) in order to identify the preferred transplant conditioning intensity (reduced-intensity conditioning [RIC] vs. MAC). In this large CIBMTR registry study we identified 4387 adult patients (age 40-65 years) who received HCT for AML (68%) or MDS (32%) between 2009 and 2015. DRI was stratified as low/ intermediate risk (1539 MAC and 999 RIC) and high/ very high risk (1121 MAC and 728 RIC). Examining the low/ intermediate risk DRI cohort (Table), RIC was associated with lower risk of TRM (HR=0.74, 95% CI 0.62-0.88; p<0.001) but significantly higher risk of relapse (HR=1.54, 95% CI 1.35-1.76; p<0.001). As a result, RFS in this cohort was significantly worse with RIC (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/ very high risk DRI cohort, RIC resulted in similar TRM (HR=0.83, 95% CI 0.68-1.00; p=0.051) but again significantly higher risk of relapse (HR=1.23, 95% CI 1.08-1.41; p=0.002). RFS in high/ very high risk DRI cohort was similar between RIC and MAC. Adjusted outcome curves for the 3 endpoints are shown in the Figure.

In this large study of HCT for AML or MDS stratified by DRI, RIC was independent predictor of lower TRM, but significantly higher risk of relapse. The MAC was an independent predictor of lower relapse in both low/ intermediate and high/very high DRI groups. However, MAC only resulted in RFS benefit in the low/ intermediate group where the magnitude of impact on relapse was not offset by the higher TRM.

In adults with AML or MDS aged 40-65 years, these data support MAC as the preferred conditioning intensity for low/ intermediate risk DRI, whereas MAC does not provide significant benefit in those with high/ very high risk DRI. Safer, yet still potent MAC regimens could benefit this higher risk group.

Disclosures

Bejanyan: Kiadis Pharma: Other: advisory board. Brunstein:Gamida: Research Funding; Astex: Research Funding; Magenta: Research Funding. Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria; Pfizer: Honoraria; Kite: Honoraria. Weisdorf:Fate Therapeutics: Consultancy; Pharmacyclics: Consultancy; Incyte: Research Funding.
Development of an Immunotherapeutic Monoclonal Antibody Recognizing DKK1-HLA-A2 Complex to Treat Human Hematologic Malignancies
Authors: Qian Jianfei , Wang Qiang , Liu Lintao , Bi Enguang , Ma Xingzhe , Su Pan , Yang Maojie , Yi Qing
Published: November 2019

Immunotherapy is a promising option for cancer treatment. Our previous studies demonstrated that DKK1 is widely expressed by various tumor cells including multiple myeloma (MM) and other hematological malignancies but not normal tissues, and DKK1 peptide (such as P20 and P66v, which bind with HLA-A2 molecule) specific cytotoxic T cells specifically kill myeloma and other cancer cells that express DKK1 and HLA-A2, but not HLA-A2+ normal cells, indicating that DKK1+ tumor cells naturally express these peptides, in the context of HLA-A2 molecules, on their surface. To develop cancer therapeutic antibodies, DKK1 peptide P20-HLA-A2 monomer was synthesized and used to immunize mice. Hybridomas secreting monoclonal antibodies (mAbs) recognizing soluble and cell surface-expressed DKKl P20-HLA-A2 complex were obtained and analyzed. The mAbs bind specifically with DKK1-expressing, HLAA2+ cancer cells but not DKK1-expressing, HLA-A2- cancer cells or DKK1- HLA-A2+ normal blood cells. The mAbs exhibited potent in vitro tumoricidal activity on HLA-A2+DKK1+ U266 multiple myeloma cells, HLA-A2+DKK1+ PC-3 prostate cancer cells and T2 cells loaded with DKK1-P20 peptides. Our results also showed that the anti-DKK1-HLA-A2 mAbs effectively lysed cancer cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which were correlated with and dependent on the surface expression of DKK1-HLA-A2 complex on cancer cells. Furthermore, anti-DKK1/HLA-A2 mAbs were also active and therapeutic in vivo. In MM xenografted SCID mouse model, the mAbs were able to eradicate U266 MM cells and more than 60% of mAb-treated mice survived for 3 months, while control mice all died within 2 months. Toxicity and safety assay in MM xenografted A2-SCID mouse model showed that the mAbs had no significant negative effects on different normal tissues. Therefore, these results support clinical development of anti- DKK1-HLA-A2 mAbs as therapeutic agents to treat hematological malignancies and possibly solid tumors that express surface DKK1-HLA-A2.

Disclosures

No relevant conflicts of interest to declare.
Human Interleukin 15 (IL15) Humanized NCG Mice Support the Human Natural Killer Cells Reconstitution and Development
Authors: Ju Cunxiang , Zhang Mingkun , Wu Dan , Tang Jing , Li Shuai , Zhao Jing , Wang Demin , Gao Xiang
Published: November 2019

NCG (GPT strain ID: T001475), one of the highly immune-deficient mouse models generated so far, is ideal for engraftment of human tissues and cells, such as patient derived tumors (PDX), human cancer cell lines (CDX), human peripheral blood mononuclear cells (PBMC) and human hematopoietic stem cells (HSCs). NK cells that are a critical component of the innate immune system have diverse biological functions, such as recognizing and killing viral-infected and neoplastic cells. Human HSCs (CD34+) could reconstitute human T but not NK cells in NCG mice. The cytokine Interleukin 15 (IL-15) plays a critical role in the generation of NK cells from HSCs. IL-15 is produced by non-lymphoid cells, including monocytes, dendritic and bone marrow stromal cells. Human and mouse IL-15 are only 70% identical to each other in primary amino acid sequence. Mouse IL-15 poorly supports the reconstitution of human NK cells.

To overcome this problem, several lines of transgenic mice that express human IL-15 (hIL-15) have been established. However, the non-physiological levels of hIL-15 expression are detrimental to human immune system reconstitution.In the current study, we developed hIL-15 knock-in in NCG mice (NCG-hIL-15), in which the mouse IL-15 (mIL-15) gene was replaced by the hIL-15 gene. We quantified the mRNA expression of hIL-15 and found that the levels of hIL-15 expression in the BM, liver, lung, and small intestine of NCG-hIL-15 mice were similar to those of mIL-15 in NCG mice.Based on these data, we expect that NCG-hIL-15 mice can efficiently support the development, maturation and function of human NK cells. In the future, we will further study human NK cell engraftment and human NK cell-mediated cancer immunotherapy in NCG-hIL-15 mice.

Taken together, our newly developed NCG-hIL-15 mice offer a novel mouse model for studying human NK cell biology and human NK-mediated cancer immunotherapy in vivo.

Disclosures

Ju: GemPharmatech Co., Ltd: Employment. Zhang:GemPharmatech Co., Ltd: Employment. Wu:GemPharmatech Co., Ltd: Employment. Tang:GemPharmatech Co., Ltd: Employment. Li:GemPharmatech Co., Ltd: Employment. Zhao:GemPharmatech Co., Ltd: Employment. Wang:GemPharmatech Co., Ltd: Employment. Gao:GemPharmatech Co., Ltd: Employment.
Real-Time Electronic Health Registry Improves Care for Children with Sickle Cell Disease
Authors: Singh Ashima , Danda Vanaja , Panepinto Julie
Published: November 2019

Objective: Published literature shows low and variable compliance with the recommended guidelines for care of children with sickle cell disease (SCD). Our objective was to use an electronic health record (EHR)-based registry to track and improve compliance with the recommendations for the pediatric population of SCD at our institution, using annual transcranial doppler screening (TCD) as an example.

Methods: We developed an in-EPIC real time registry for children with SCD in the year 2016 to enhance point of care and improve quality. Since 2017, we have been conducting plan-do-study-act (PDSA) cycles using the registry to improve TCD compliance. We extract data quarterly to examine TCD rates and share with the clinical team the list of children who have not received a TCD screening in the past 18 months. This allows the clinical team to provide case-management to reduce non-compliance. We recently added Child Life support to increase TCD compliance among children <7 years. We use control charts to examine TCD rates after the aforementioned interventions. We also continually refine the registry to broaden the provision of quality care to the patient population.

Results: One year into the registry, which we considered baseline and the start of the first PDSA cycle, 63% of children were compliant with the recommendation of an annual TCD screen. The TCD rates steadily increased to 80% by the third-quarter of 2017. We observed a dip in TCD rates by the second-quarter 2018 (66%), felt to be in part driven by failure of screening young children. Since the initiation of Child Life Support for young children, the overall TCD rates increased to 74% (first-quarter 2019). Our data demonstrate a sustained improvement in TCD rates since 2016 and meet criteria for special cause variation (Figure 1). We have recently added other metrics such as acute care encounters external to our institution, magnetic resonance imaging, and an indicator for active hydroxyurea use to the registry.

Conclusion: Use of an EHR-based registry to track and provide feedback on quality of care metrics such as annual TCD screening can result in sustained improvement in compliance with the recommended guidelines. Preliminary evidence indicates that Child Life involvement further improves TCD rates. Future work will determine if audit and feedback for other metrics added to the registry can improve compliance and improve outcomes.

Disclosures

Panepinto: NIH: Research Funding.
Intravenous Iron Infusions in Pediatric Patients: A Single Institution Assessment of Efficacy and Adverse Effects of IV Iron Infusions
Authors: Nestor Jennifer A , Afridi Faraz A , Suarez Richard , Karem Joey Bou , Hardiman Michael , Hunter Krystal , Rickette Christine , Ahmed Rafat
Published: November 2019

Background:

Iron deficiency, even without a diagnosis of anemia, can be neurodevelopmentally dangerous in pediatric populations. Oral iron supplementation has been the treatment of choice but is associated with poor adherence for several reasons including metallic taste of the tablets, gastric irritation, severe constipation, and daily dosing for several weeks. Intravenous iron has been safely used in adult populations for iron supplementation, but has less commonly been used in pediatric populations. It is hypothesized that pediatric patients with iron deficiency anemia (IDA) who receive intravenous iron infusions will show normalization of hematologic parameters.

Methods:

EMR of patients aged 1-21 who received at least one intravenous iron infusion at Cooper University Hospital between 2016 and January 2019 were reviewed for retrospective data collection. Pre-infusion lab values including Hgb, MCV, RBCs and RDW were compared to post-infusion values to determine if values normalized after intravenous iron infusion. Patient demographics including ethnicity, cause of IDA, prior oral iron treatments, and adverse effects of oral and IV iron were analyzed.

Results:

There were 33 subjects in this study. The average age of the subjects was 12.8 (+/- 5.1) years of age and 79% were female. The most prevalent indication for IV iron was menorrhagia (55%), while GI issues were 18% and insufficient diet accounted for 27%. The mean baseline HGB was 8.3 (+/- 1.7) while the mean final HGB increased to 11.5 (+/- 1.4) (p<0.001). The mean baseline MCV was 69.2 (+/- 9.3) and the mean last MCV was 76.1 (+/- 6.8) (p<0.001). The mean baseline RBC was 4.2 (+/- 0.82) and the mean last RBC was 4.9 (+/- 0.6) (p<0.001).

Conclusion:

IV iron sucrose infusions administered to pediatric outpatients were safe and effective in children and adolescents with IDA. Adherence to intravenous iron did not significantly improve. Hematologic parameters improved with infusions. Further analysis of patient demographics and characteristics of diagnosis needs to be performed to elucidate benefits of this therapy. As a single institution study, the results are limited to a regional patient population and their specific demographics.

Disclosures

No relevant conflicts of interest to declare.
Hematocrit and Incidence of Venous Thromboembolism
Authors: Cushman Mary , Wang Wendy , Parikh Romil , Lutsey Pamela L , Beckman Joan D , Folsom Aaron R
Published: November 2019

Background. Polycythemia vera patients with high hematocrit have increased risk of venous thromboembolism (VTE). We tested whether high hematocrit in the general population is also associated with elevated VTE risk.

Methods. The prospective Atherosclerosis Risk in Communities (ARIC) Study performed a complete blood count in 13,891 adults aged 45-64 at baseline in 1987-89. We identified and validated incident hospitalized VTEs through 2015, with provoked VTE defined as occurring within 90 days of surgery, trauma, immobilization or with cancer. We performed proportional hazards regression analyses using race-sex specific categorization of hematocrit percentiles (i.e., <5, 5-24.9, 25-74.9, 75-94.9, and 95-100 percentiles, with the 25-74.9th percentile serving as the reference group).

Results. At baseline, higher hematocrit was associated with smoking prevalence, greater pack years smoked, higher body-mass index and higher prevalence of diabetes. With 26 years median follow-up, 800 participants had incident deep vein thrombosis of the leg and/or pulmonary embolism. The figure shows a J-shaped association of hematocrit with VTE incidence. The VTE incidence at the highest level of hematocrit was approximately double that at the mid level. Low hematocrit also was associated with elevated VTE incidence but the confidence interval overlapped 1. The Table shows modeling results. Accounting for other risk factors, the risk of overall VTE was elevated 72% for participants above the 95th percentile of hematocrit compared with the reference. Specifically, hazard ratios (95% confidence interval) of incident VTE were 1.27 (0.91,1.76), 1.06 (0.87,1.28), 1 (reference), 1.17 (0.98, 1.40) and 1.72 (1.30, 2.27) across the five hematocrit percentiles, adjusted for age, race, sex, body mass index, and other potential confounding variables including smoking status and pack-years. The association of high hematocrit with VTE was limited to provoked VTE, with little evidence for unprovoked VTE. Results were similar for hemoglobin (not shown).

Discussion. High hematocrit and hemoglobin in a general middle-aged population sample were associated with increased long-term risk of VTE, particularly provoked VTE. The reasons for this pattern require further study.

Disclosures

No relevant conflicts of interest to declare.
Decitabine Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft Versus Host Disease
Authors: Li Yuan , Wang Qing Ya , Liang Ze Yin , Yin Yue , Liu Wei , Wang Qian , Dong Yujun , Sun YuHua , Xu Wei Lin , Ren Hanyun
Published: November 2019

Objective: To evaluate the role of Decitabine in the allo-HSCT conditioning regimen for intermediate- and high-risk patients with MDS or AML.

Methods:Retrospective analysis of data pertaining to 76 intermediate and high-risk patients with MDS or AML who underwent allo-HSCT between December 2005 and June 2018 at the Peking University First Hospital. Forty patients received Decitabine containing conditioning regimen before transplantation, while thirty-six patients received regimen without Decitabine.

Results: Overa median follow up of 40 months(range, 1 to 155), the incidence of grade II to IV acute graft versus host disease was 12.5% in the Decitabine group and 41.7% in the non-Decitabine group (P=0.003). On multivariate analysis, Decitabine containing conditioning regimen was found to protect against grade II to IV aGVHD (HR=0.275, 95% confidence interval 0.098-0.770,P=0.014). Incidence of respiratory infection in the Decitabine and non Decitabine groups was 22.5% and 52.78%, respectively (P=0.012). No significant between group difference was observed with respect to 3-year OS, DFS, or RR (P=0.980, 0.959, and 0.837, respectively), while the median relapse time was longer in the Decitabine group [7 months (range, 2 to 12) versus 3 months (range, 2 to 4), P=0.171]. Decitabine containing conditioning showed a tendency for lower relapse rate among higher risk patients, as assessed by IPSS R; however, the between-group difference was not statistically significant (P=0.085).

Conclusions: Inclusionof Decitabine in the conditioning regimen for allo-HSCT in intermediate- and high-risk patients may lower the incidence of aGVHD and respiratory infections, and contribute to longer median relapse time.

Disclosures

No relevant conflicts of interest to declare.