Socially Excluded Persons in Ireland Have an Increased Annual Risk of Hospitalisation Due to Venous Thromboembolic Disease

Introduction Social exclusion in Ireland is strongly associated with injecting drug use, particularly injection of opiates into the groin: a strong risk factor for venous thromboembolism (VTE) (O'Reilly et al, 2015). Ní Cheallaigh et al (2017) reported a high burden of disease in socially excluded individuals in Ireland that can be effectively addressed by dedicated service planning and care provision. VTE in socially excluded persons has been identified by our group as a key knowledge gap. We have generated preliminary data demonstrating that socially excluded people account for a significant proportion of patients presenting with VTE in Dublin. Methods We extracted national Hospital InPatient Enquiry (HIPE) data from Health Atlas Ireland using the methods outlined in Kevane et al (2019). We identified individuals as "socially excluded persons" if their records contained one or more of the variables identified by Aldridge et al (2018): homeless individuals, prisoners, sex workers and individuals with substance use disorders. We identified all emergency inpatient hospital admissions for those with any diagnosis of VTE during 2017 using VTE-associated ICD-10 codes. Results There were 494,972 emergency inpatient admissions in patients >16 years during this 12 month period, of which 5,717 (1.2%) had a VTE diagnosis (55% of which were DVTs). 306 (5.3%) of hospital episodes with VTE occurred in socially excluded individuals. Applying maximum and minimum assumptions on the estimated population denominator we estimated that overall the annual incidence rate of VTE-related hospitalisation per person was approximately 10-fold higher in socially excluded individuals when compared to the general population (in which it was 0.12%). Conclusions This is the first time that an approximately ten-fold increase in the risk of hospitalisation due to VTE has been shown to be associated with social exclusion. This information was generated from national data, using surrogate identifiers for socially excluded persons. We hypothesise that detailed characterisation of VTE events in socially excluded clients will permit improved service planning and care provision for these vulnerable patients, enabling better VTE prevention and management. This may save lives and prevent the disabling and common long-term consequence of post-thrombotic syndrome with debilitating leg ulcers, which in this population results in numerous admissions and severe mobility issues. Planning such initiatives has the potential to reduce morbidity and mortality, improve quality of life but also to reduce hospital admissions (which are hugely over-represented in this patient group), save costs and resources and most importantly results in more equitable health care for socially excluded patients. Disclosures Ewins: Amgen: Other: Conference Fees & Travel Expenses; Bayer: Other: Conference Fees & Travel Expenses. Ni Ainle:BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding; Actelion: Research Funding. Cliona:Pfizer: Research Funding; MSD: Other: Travel Expenses.

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Higher Rates of Death and Major Bleeding Highlight the Inequities That Exist in the Care of People with Venous Thromboembolism Who Experience Social Exclusion: Findings from a Prospective Registry of 79735 Patients (RIETE)

Blood ◽

10.1182/blood-2019-130745 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4677-4677

Author(s):

Karl Ewins ◽

Fionnuala Ni Ainle ◽

Cliona Ni Cheallaigh ◽

Eoghan Dunlea ◽

Sarah Kelliher ◽

...

Keyword(s):

Liver Disease ◽

Drug Use ◽

Board Of Directors ◽

Social Exclusion ◽

Major Bleeding ◽

Research Funding ◽

Injecting Drug Use ◽

Service Planning ◽

Advisory Committees ◽

Socially Excluded

Background Social exclusion, experienced by vulnerable people at the margins of society, causes severe health inequity with dramatically increased risks of chronic disease and reductions in life-expectancy. Health services are not designed to meet the complex needs of socially excluded people (SEP). SEP are frequently unintentionally excluded from large observational studies such as household surveys and surveys requiring active participation (Levitas et al, 2007). This lack of data deepens inequity. Social exclusion in Ireland is strongly associated with injecting drug use, a strong risk factor for venous thromboembolism (VTE) (O'Reilly et al, 2015). Although an increased prevalence of VTE in lower socioeconomic groups has been described (Zoller et al, 2012), the impact of social exclusion and marginalisation on VTE has never been characterised in detail. The Registro Informatizado de Enfermedad TromboEmbólica (RIETE Registry) is the world's largest database on patients with VTE. It was commenced in 2001 and continues to collect prospective data on consecutive patients presenting to hospital with acute VTE events. Patients are followed longitudinally, for a minimum of three months (Bikdeli et al, 2018). One objective of the registry is to provide information on the natural history of VTE - particularly in subgroups of patients who would not usually be recruited to randomised clinical trials. Methods Our group has generated preliminary data (submitted separately to ASH 2019) which demonstrate that people with social exclusion can be identified from large national and international datasets using surrogate identifiers. The RIETE registry already collects several of these data elements that can be used to identify people who are socially excluded: HIV infection (which is strongly associated with injecting drug use), liver disease, chronic alcoholism and chronic psychiatric illness. We adapted the methodology developed in the Irish dataset and interrogated the RIETE registry utilising the available surrogate identifiers. We aimed to estimate the prevalence of social exclusion amongst patients with VTE, and to determine their clinical characteristics, treatment details and outcomes, with the ultimate goal of informing future service-planning and care-provision to this vulnerable group. Results At the time of interrogation of the RIETE registry, 79735 patients with VTE had been enrolled in 24 countries worldwide. Of these, 9211 (12%) met our criteria for SEP due to the presence of one or more of our surrogate identifiers. Of these, 60% presented with pulmonary embolism vs 52% in the non-SEP group (P<0.001), and SEP were more likely to have other medical co-morbidities. Major bleeding was more frequent in the SEP group (5.36 vs 3.55 events per 100 patient-years; HR 1.51 (1.35-1.69)), particularly in those with liver disease (8.70 events per 100 patient years) or psychiatric disorders (5.31 per 100 patient years). Death occurred more frequently in the SEP group (17.9 vs 12.0 events per 100 patient years; HR 1.49 (1.40-1.58)), and recurrent VTE occurred most frequently in those with HIV infection (4.31 events per 100 patient-years) and liver disease (4.46 events per 100 patient years, compared with 3.46 in the non-SEP group). Although Vitamin K Antagonists were used for longer term therapy in the majority of both patient groups (50% SEP, 63% non-SEP), the proportion who received low molecular weight heparin was higher in the SEP group (36% vs 26%). This was highest in the HIV infected subgroup, our identifier that best correlates with injecting drug use. Conclusions Social exclusion, as determined by the use of surrogate markers from a large prospective VTE registry, was associated with a higher overall incidence of death and major bleeding in patients treated for VTE. These data highlight the inequities experienced by this vulnerable patient group, demonstrating the need for increased funding for service planning and care provision to better prevent and manage VTE. This can lead to reductions in hospital admissions and costs, but ultimately to the provision of equitable healthcare for SEP. Disclosures Ewins: Bayer: Other: Conference Fees & Travel Expenses; Amgen: Other: Conference Fees & Travel Expenses. Ni Ainle:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Leo Pharma: Research Funding; Boehringer: Membership on an entity's Board of Directors or advisory committees; Actelion: Research Funding. Ni Cheallaigh:MSD: Other: Travel Expenses; Pfizer: Research Funding.

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A Refined Model of HLA-DP Permissiveness Improves Stratification of Acute Graft-Versus-Host Disease Risks after Unrelated Hematopoietic Cell Transplantation: A Retrospective Study from the CIBMTR

Blood ◽

10.1182/blood-2021-146957 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2890-2890

Author(s):

Esteban Arrieta-Bolanos ◽

Pietro Crivello ◽

Meilun He ◽

Tao Wang ◽

Shahinaz M. Gadalla ◽

...

Keyword(s):

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Patent Application ◽

Multivariable Analysis ◽

Significant Proportion ◽

Cell Epitope ◽

Hematopoietic Cell ◽

Advisory Committees

Abstract Introduction: Permissive HLA-DPB1 mismatches defined by the T-cell epitope (TCE) model are an established selection criterion for unrelated donors in allogeneic hematopoietic cell transplantation (alloHCT) (Dehn et al. Blood 2019). Based on biological evidence, the TCE model has classified HLA-DPB1 alleles into at least three functional groups, one of which (TCE group 3; TCE3) houses a large number of alleles with different structural and functional characteristics. We have recently shown that structurally close HLA-DP allotypes have similar peptide-binding motifs and share a significant proportion of their immunopeptidomes, the latter being fundamental for permissiveness (Meurer & Crivello et al. Blood 2021). Hence, we hypothesized that HLA-DPB1 mismatches involving alleles that encode structurally distant allotypes within TCE3 could be less permissive than those involving alleles that encode structurally closer allotypes, and thus have a differential impact on clinical outcomes. Methods: Multidimensional scaling techniques were used to compare 28 polymorphic positions (amino acids 8-215) among 51 alleles present in a cohort of 5,140 10/10 matched patient-donor pairs who received a first alloHCT for AML, ALL, or MDS between 2008-2017. Based on these analyses, TCE3-permissive mismatches (N=2,216) were further stratified into those involving structurally close or more distant combinations and compared with HLA-DPB1-matched (N=785) and non-permissively mismatched (N=2,023) pairs. These models were tested in parallel to the "classical" TCE model considering permissive mismatches (N=2,332) as a whole, to determine their association with overall survival (OS), disease-free survival (DFS), treatment-related mortality (TRM), primary disease relapse, and acute (a) and chronic (c)GVHD. Kaplan-Meier analysis and log-rank testing were used to compare the median OS and DFS. The incidences of GVHD, relapse and TRM were compared using competing risks and Gray's test. The effect of HLA-DPB1 mismatch on time-to-event outcomes was modelled by Cox regression after adjusting for confounders and testing for the proportional hazards assumption. Results: Within TCE3, we identified a subgroup of 4 frequent and structurally as well as functionally closely related alleles (i.e. DPB1*02:01, 04:01, 04:02, 23:01) that form a separate cluster (Figure 1A). These "core" alleles have similar bound-peptide motifs (van Balen et al. J Immunol 2020) and can be distinguished from other alleles in TCE3 in terms of the strength of in vitro alloreactive responses elicited from permissive responders (Meurer et al. Front Immunol 2018). Moreover, principal component analysis identified the HLA-DP 84-87 DEAV/GGMP motif as a major factor driving structural variability among TCE3 alleles (not shown). We used these observations to stratify TCE3 permissive mismatches in the allo-HCT cohort into "core" (N=930) and "non-core" (N=1,286) or into DEAV/GGPM-matched (N=1,209) and mismatched (N=1,007) pairs (Figure 1B). Multivariable analysis confirmed the association of aGVHD2-4 for the classical TCE model of non-permissive mismatching (p<.0001) and revealed a trend in DEAV/GGPM and "core"/"non-core" TCE3-permissive models. When compared to HLA-DPB1 allele matched pairs the risks of aGVHD2-4 increased progressively with "core" TCE3-permissive (HR 1.12 [0.98-1.28]; p=0.1012), "non-core" TCE3-permissive (HR 1.24 [1.06-1.46]; p= 0.0082), and non-permissive mismatches (HR 1.32 [1.16-1.50]; p<.0001) (Figure 1C, "core" vs. "non-core" HR 0.90 [0.80-1.01]; p=0.062). Similar albeit less significant results were obtained with the DEAV/GGPM model. The "core"/"non-core" TCE3 model was also associated with TRM with alloHCT from "core" TCE3-permissive donors showing lower risks of TRM than "non-core" TCE3-permissive (HR 0.82 [0.70-0.96]; p=0.0118) and non-permissive donors (HR 0.78 [0.68-0.88]; p=0.0002). Conclusion: Our results suggest that structural differences within TCE3 that reflect functional divergence and differential immunogenicity of alleles in this group associate with the risks of aGVHD and TRM after alloHCT. Hence, within the population of 10/10 matched donors, selection of "core" TCE3-permissive donors might reduce patient morbidity after transplantation. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

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Immune Thrombocytopenia Complications: Implications on Length of Stay and and Mortality

Blood ◽

10.1182/blood-2018-99-115825 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3512-3512

Author(s):

Manoj P Rai ◽

Prabhjot Singh Bedi ◽

Justin D. Kaner ◽

Prajwal Dhakal ◽

Samanjit Kaur Kandola ◽

...

Keyword(s):

Length Of Stay ◽

Board Of Directors ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Significant Proportion ◽

Prolonged Treatment ◽

Coagulation Disorders ◽

Advisory Committees ◽

Risk Of Death ◽

Management Of Complications

Abstract Introduction: Immune thrombocytopenia (ITP) is an autoimmune phenomenon causing increased destruction and insufficient platelet production. ITP can be a healthcare burden due to prolonged treatment (medical and sometimes surgical = splenectomy) required to prevent the relapse and frequent hospitalizations for management of complications such as epistaxis, gastrointestinal bleeding (GIB) or intracranial hemorrhage (ICH). In addition, septicemia and coagulation disorders can occur related to therapy. In this study we analyzed demographics among inpatient admissions with ITP and the variation of length of stay (LOS) and mortality with different complications. Methods: We performed a retrospective cohort analysis of the National Inpatient Sample 2014 Database (HCUP-NIS). Patients were included in the study if they had a primary or secondary diagnosis of ITP and age >18 years. We performed descriptive statistics to characterize the cohort in terms of personal demographic factors (age, race, sex, insurance type, community level income level), hospital characteristics (size, region, teaching status, and urban or rural location). The cohort was classified on based on splenectomy status using procedure diagnosis code. The cohort was further analyzed for complications such as coagulation disorders, GIB, ICH, septicemia and epistaxis using their principal diagnosis. Furthermore, we also looked at the variation in LOS and mortality among them. Univariate and multivariate regression analysis were performed to determine statistical significance. All analyses applied the HCUP-NIS weights. Results: There were 11,535 patients in the cohort. Most were white (64.4%), females (57.95%), and aged < 60 years (55.6%). A significant proportion were covered by Medicare (41.33%). Most care was delivered in large hospitals (55.17%), that were disproportionately urban (94.4%) or teaching (70.61%) institutions. The greatest segment of patients were in the South Atlantic region (20.8%). Epistaxis occurred in 15.3% of patients, GIB in 3.12%, ICH in 0.41%, and septicemia in 0.99%. The mean LOS was 4.73 days (95% CI 4.49 to 4.97). Mean LOS was highest in patients with septicemia (12.3 days), followed by GIB (8.98 days) and ICH (7.99 days), and epistaxis and coagulation disorders (6 days each). LOS was significantly shorter in patients who had undergone splenectomy (AMD -10.67 95% CI-18.32 to -3.03), and longer with septicemia (AMD 9.06 95% CI 1.84 to 16.27). Compared to Medicare, other insurances statuses had shower LOS: uninsured (AMD -6.60 95% CI -10.76 to -1.39), Medicaid (AMD -3.57 95% CI -7.07 to -0.086), and private (AMD -2.67 95% CI -5.39 to 0.037). Risk of death was much higher with GIB (OR 227 95% CI 7.63 to 6757.48, p=0.002) and ICH (OR 100.88 95% CI 10.27 to 990.91, p <0.01). Discussion: Treatment and complications significantly impact LOS and mortality for patients with ITP. Splenectomy is associated with decreased LOS, presumably because of rapid improvement in platelet counts, while septicemia is associated with increased LOS likely related to intensity of service delivered. Insurance types are also independently associated with LOS. It is unclear if this is related to differences in biologic factors (e.g. age, comorbidities, frailty), or process factors (e.g. care management practices, payment incentives). Table. Table. Disclosures Bussel: Amgen Inc.: Consultancy, Research Funding; Momenta: Consultancy; Prophylix: Consultancy, Research Funding; Protalex: Consultancy; Uptodate: Honoraria; Rigel: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Marks:Lilly: Membership on an entity's Board of Directors or advisory committees; UPMC: Employment; Heron: Membership on an entity's Board of Directors or advisory committees; Odonate: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Equity Ownership.

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Elective Vs Non-Elective Hospital Admissions By Patients with Multiple Myeloma in England 2014 - 2018

Blood ◽

10.1182/blood-2018-99-114736 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4743-4743

Author(s):

Karthik Ramasamy ◽

Spyros Kolovos ◽

Guido Nador ◽

Rosemarie Finley ◽

Matthew Streetly ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Hospital Admissions ◽

Healthcare Resource ◽

Resource Utilisation ◽

Advisory Committees ◽

Number Of Patients ◽

The Impact ◽

Hospital Use

Abstract Introduction: Multiple myeloma (MM) is associated with high healthcare resource utilisation. Better understanding of the hospital use by patients with MM is needed to plan future resource allocation to care for these patients. The aim of this study was to characterise the hospital use by patients with MM in the English National Health Service (NHS). Methods: Routinely-collected aggregate hospital admissions data from patients with MM were used from all 451 hospital trusts in the English NHS. This included elective and non-elective hospital admissions from April 1st 2014 to March 31st 2018. Patients were identified using the ICD-10 code for MM (C90.0) as either primary or secondary diagnosis. The number of admissions, number of patients, procedures, and total NHS hospital costs (based on Healthcare Resource Groups and NHS national tariff) were extracted alongside data to identify what percentage of the total NHS admissions are related to MM. Elective admissions were defined as admissions where the decision to admit preceded the time of the actual admission. Results: There were 754,345 admission records reported during the period of analysis from 17,555 women and 24,290 men. Of these, 675,400 (89%) were elective and 78,945 non-elective admissions. The total cost during the period analysed was £183,389,143 for elective and £227,650,088 for non-elective admissions. For elective admissions, 65% of the costs were for day-cases. Despite non-elective admissions constituting only 11% of all admissions, they accounted for 55% of the total hospitalisation costs. Over the period of analysis, elective admissions increased in average by 4.5% per year whilst the average yearly increase in costs was 1.5%; for non-elective hospitalisations, these figures were 4.1% and 9.0%, respectively (Figure). Of the total number of non-elective admissions over the study period, 58% were by men. Most of the procedures for elective admissions were related to chemotherapy and for non-elective ones the majority regarded radiology. While only 0.2% of all patients admitted to the NHS between April 2014 and March 2018 had a MM code, they accounted for 1% of all admission records and 0.5% of all inpatient NHS costs. During this period, patients with MM had on average 19 elective and 3 non-elective admissions per year, compared to 3 elective and 2 non-elective admissions per year per person for all patients admitted to the NHS. Conclusions: MM is associated with a large number of hospital admissions in the English NHS, relative to the low incidence of the disease. While the majority of the hospital admissions are elective, non-elective admissions accounted for the majority of costs. The impact of non-elective admissions should be included when assessing the economic burden of MM and the benefits from novel therapies. Further research is needed to understand the timing of non-elective admissions in the natural history of MM. Disclosures Ramasamy: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nador:Amgen: Research Funding. Kishore:Celgene: Honoraria; Takeda: Honoraria, Other: travel support. Rabin:Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Other: Travel support , Speakers Bureau; Celgene: Speakers Bureau. Yong:Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Honoraria. Ashcroft:Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amaris Medical: Consultancy, Honoraria. Bowcock:Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Takeda: Consultancy. Drayson:Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Large Population Dataset Linkage to Understand Evolving Practice in Red Cell and Platelet Transfusion and Clinical Outcomes in Patients with Myelodysplastic Syndromes (MDS): A 15-Year Study

Blood ◽

10.1182/blood-2021-147132 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3255-3255

Author(s):

Allison Mo ◽

Jake Shortt ◽

Erica M. Wood ◽

Zoe K McQuilten

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Platelet Transfusion ◽

Hospital Admissions ◽

Advisory Committees ◽

Disease Modifying Therapies ◽

Transfusion Requirements ◽

Rbc Transfusion ◽

Over Time ◽

Platelet Transfusions

Abstract Aim: Transfusions are frequently administered for anemia and thrombocytopenia in MDS. However, evidence to guide transfusion remains sparse, along with data about real-world MDS transfusion practices, transfusion-related outcomes and changes over time with increasing access to disease-modifying therapies. In Australia, from 2011, 5-azacitidine was funded through the Pharmaceutical Benefit Scheme (PBS) for patients with IPSS classification intermediate-2 or high-risk MDS, or Chronic Myelomonocytic Leukemia-2 (CMML-2). Australian Patient Blood Management (PBM) guidelines were also first published in 2011. We aimed to characterise red blood cell (RBC) and platelet transfusion practices, and transfusion-related outcomes of MDS and CMML patients over a 15 year period, and explore whether access to disease-modifying therapies or the introduction of PBM guidelines impacted on transfusion requirements. Methods: Retrospective longitudinal cohort study including all patients with MDS/CMML admitted to hospitals in Victoria, Australia's second most populous state, from 2002-2017. Data linkage from the Victorian Admissions Episode Dataset (VAED) (contains data from all public and private hospital admissions in Victoria, including all transfusion episodes), the Victorian Cancer Registry and the Victorian Death Index was performed. We analysed transfusion episodes and outcome events (cardiac ischemia/failure, transfusion reactions, bleeding). Results: 6771 patients with a diagnosis of MDS/CMML reported to the Cancer Registry were included (5970 MDS; 801 CMML). The cohort was elderly (>50% aged 70y and over) and predominantly male (male 61%; female 39%). The majority of patients had a low number of comorbidities (Charlson Comorbidity Score: 60% low (0-2); 32% moderate (3-5); 8% high (≥6)). Of the 179 patients on 5-azacitidine, 38 (21.2%) commenced prior to 2011 and 141 (78.8%) from 2011 onwards. Patients on 5-azacitidine were more likely to be RBC transfusion dependent (TD) (defined as 2 or more RBC transfusions within 16 weeks) (77.7.1% vs 49.9%, p<0.001) and receive platelet transfusions (54.2% vs 28.6%, p<0.001). During the study period, the patients had a total of 142,765 hospital admissions. 66,068 (46.3%) admissions involved RBC transfusion, with median 3 admissions (IQR 1-10) per patient and median 14 days (IQR 14-33) between transfusions. 3433 (50.7%) of patients were RBC transfusion-dependent (TD). Comparing pre-and post-2011, the proportion of admissions involving RBC transfusion, median number of RBC transfusion admissions per patient, and rates of RBC-TD decreased (table 1). Cardiac events were common, and more frequent in RBC-TD patients (acute cardiac ischemia 14.6% vs 10.3%, p<0.001; acute cardiac failure 27.3% vs 14.1%,p<0.001). 10,049 (7.0%) admissions involved platelet transfusion. Platelet transfusion admissions increased over time (table 1). Median time between platelet transfusions was 7 days (IQR 4-16). 2436 patients (36.0%) experienced bleeding, including 51.3% of platelet-transfused patients. The commonest bleeding site was gastrointestinal (n=1388, 20.5%). Intracranial bleeding occurred in 175 patients (2.6%). 300 patients (4.4%) died from bleeding complications, with higher bleeding-related mortality in platelet-transfused patients (7.0% vs 3.4%, p<0.001) and RBC-TD patients (5.2% vs 4.0%, p=0.001). Conclusion: This study highlights the high transfusion burden in MDS patients, and related adverse cardiac and bleeding outcomes and mortality. RBC transfusion requirements reduced over time but platelet transfusions increased. This may be related to changing availability or use of MDS therapies, or clinical transfusion decision-making practices, or both - although national PBM guidelines do not specify a particular hemoglobin threshold for chronically transfused MDS patients, clinicians may be extrapolating from recommendations for restrictive transfusion thresholds in other settings (e.g. critical care, perioperative transfusion). These data will help design future MDS transfusion trials, which should include quality-of-life and health economics outcomes, given the burden of transfusion on these elderly patients. Figure 1 Figure 1. Disclosures Shortt: Amgen: Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Wood: Amgen, Celgene, Gilead, Janssen, Novartis, Sanofi, Takeda: Research Funding; Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda.: Other: The Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) has received funding from Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda. .

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Secondary Erythrocytosis Is Phenotypically Distinct from Polycythemia Vera but Associated with Comparable Rates of Thrombosis at Diagnosis

Blood ◽

10.1182/blood-2020-141835 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-7

Author(s):

Eliane Nguyen ◽

Natasha Szuber ◽

Michael Harnois ◽

Lambert Busque ◽

Luigina Mollica ◽

...

Keyword(s):

Bone Marrow ◽

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Thrombotic Event ◽

Significant Proportion ◽

World Health ◽

Chronic Obstructive ◽

Advisory Committees

Background: Since lowering the hemoglobin (Hb) and hematocrit (Hct) diagnostic thresholds for polycythemia vera (PV) to 165 g/L and 49% in men and 160 g/L and 48% in women respectively, by the World Health Organization (WHO) in 2016 (Blood. 2016;127:2391), hematologists have witnessed an increase in referrals for erythrocytosis, a significant proportion of which are found to have secondary erythrocytosis (SE). This has yielded novel challenges as comprehensive data on SE and reports comparing SE vs PV are scarce. Further, data regarding thrombosis in SE have been inconsistent (Clin Appl Thromb Hemost. 2013;19:363; J Clin Anesth. 1991;3:99; Ann Hematol. 2016;95:233). Methods: This multicentric retrospective study included PV patients enrolled in a pan-provincial registry of the chronic myeloid leukemia and myeloproliferative neoplasms Quebec Research Group (GQR LMC-NMP). SE patients were recruited from the Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada. PV diagnosis was per WHO 2016 criteria (Blood. 2016;127:2391). SE was defined as sustained elevation in Hb and/or Hct above WHO thresholds for PV with negative JAK2V617F testing and non subnormal serum erythropoietin (Epo) levels. Epo levels were drawn in therapy-naïve patients within 3 months of diagnosis using a standard immune-enzymatic assay (reference 3-30 mIU/mL). Endogenous erythroid colony assays used standard methods. JAK2 mutation screen and risk-stratification for PV were according to convention. Standard statistical methods were used to assess variables across i) SE and PV groups, and ii) subjects having experienced a thrombotic event vs no thrombosis. JMP® Pro 13.0.0 software was used for all analyses (SAS Institute, Cary, NC, USA). Results: Among 102 informative cases of erythrocytosis, 36 (35%) were SE and 66 (65%) were PV. Median age was significantly lower in the SE (57 years old; range 19-76) vs PV group (63.5 years old; range 20-89) (p=0.005), with a preponderance of males (75% in SE vs 45% PV; p=0.004). Median serum Epo levels were normal in the SE cohort (10.3 mIU/mL; range <1-148) vs subnormal in PV patients (2.3 mIU/mL; range <1-14.1) (p<0.0001). At diagnosis, SE vs PV patients had significantly lower baseline platelets (191 vs 417 x 109/L; range 125-476 vs 120-995), leukocyte counts (7.2 vs 10 x 109/L, range 4.1-15.1 vs 4.5-20.5) and lactate dehydrogenase (LDH) (182 vs 247 U/L, range 126-316 vs 157-874) (p<0.0001). Further, SE vs PV cohorts displayed less frequent palpable splenomegaly (6% vs 23%; p=0.02), higher median BMI (33.4 vs 26; p=0.02), and an excess of active smokers (31% vs 12%; p=0.03) (Table 1). The most prevalent etiology of erythrocytosis in the SE cohort was idiopathic, reported in 50% of cases (n=18), followed by smoking/chronic obstructive pulmonary disease in 22.2% (n=8), smoking plus additional factors in 8.3% (n=3), sleep apnea, polycystic kidney disease, or a combination of the latter two in 5.6% each (n=2 each) and post kidney transplant in 2.7% (n=1) (Table 1). Nearly as many SE (n=11, 31%) as PV patients (n=26, 39%) were exposed to bone marrow sampling (p=0.37) and SE patients were frequently managed with phlebotomy (42% vs 76% PV, p=0.0007) and aspirin therapy (56% vs 93% PV, p<0.0001) (Table 1). SE and PV populations had similar rates of thrombosis at/prior to diagnosis including events in 9 (25%) SE and 19 (29%) PV patients (p=0.68), both predominantly arterial (n=7 and n=16 respectively; p=0.58) (Table 2). History of thrombosis at any time in both groups clustered significantly with older age (p=0.001), hypertension (p<0.0001), diabetes (p=0.01), obesity (p=0.01) and hyperlipidemia (p<0.0001) (Table 3). Conclusions: SE patients are significantly younger, more likely to be male, active smokers, and obese, with normal-high Epo, normal LDH, and exceedingly rare leukocytosis and thrombocytosis, discriminating them phenotypically from PV patients. Importantly, rates of thromboembolic events prior to/at diagnosis are comparable in SE vs PV, suggesting that SE may not be benign from a thrombosis standpoint. Classic cardiovascular risk factors significantly cluster with thrombosis risk, emphasizing the importance of controlling these variables in both cohorts. Finally, a significant portion of SE patients are subject to bone marrow sampling and, though controversial, treatment with phlebotomy and aspirin, highlighting the need for formal studies to guide management in this population. Disclosures Szuber: Novartis: Honoraria. Busque:BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Assouline:Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Olney:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Distinct Gene Expression Signatures in Patients with Richter's Syndrome and Chronic Lymphocytic Leukemia with Prior Exposure to Ibrutinib

Blood ◽

10.1182/blood-2020-136172 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Hanyin Wang ◽

Shulan Tian ◽

Qing Zhao ◽

Wendy Blumenschein ◽

Jennifer H. Yearley ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Activation ◽

Expression Profiles ◽

Lymphocytic Leukemia ◽

B Cell Activation ◽

Advisory Committees ◽

Upregulated Genes

Introduction: Richter's syndrome (RS) represents transformation of chronic lymphocytic leukemia (CLL) into a highly aggressive lymphoma with dismal prognosis. Transcriptomic alterations have been described in CLL but most studies focused on peripheral blood samples with minimal data on RS-involved tissue. Moreover, transcriptomic features of RS have not been well defined in the era of CLL novel therapies. In this study we investigated transcriptomic profiles of CLL/RS-involved nodal tissue using samples from a clinical trial cohort of refractory CLL and RS patients treated with Pembrolizumab (NCT02332980). Methods: Nodal samples from 9 RS and 4 CLL patients in MC1485 trial cohort were reviewed and classified as previously published (Ding et al, Blood 2017). All samples were collected prior to Pembrolizumab treatment. Targeted gene expression profiling of 789 immune-related genes were performed on FFPE nodal samples using Nanostring nCounter® Analysis System (NanoString Technologies, Seattle, WA). Differential expression analysis was performed using NanoStringDiff. Genes with 2 fold-change in expression with a false-discovery rate less than 5% were considered differentially expressed. Results: The details for the therapy history of this cohort were illustrated in Figure 1a. All patients exposed to prior ibrutinib before the tissue biopsy had developed clinical progression while receiving ibrutinib. Unsupervised hierarchical clustering using the 300 most variable genes in expression revealed two clusters: C1 and C2 (Figure 1b). C1 included 4 RS and 3 CLL treated with prior chemotherapy without prior ibrutinib, and 1 RS treated with prior ibrutinib. C2 included 1 CLL and 3 RS received prior ibrutinib, and 1 RS treated with chemotherapy. The segregation of gene expression profiles in samples was largely driven by recent exposure to ibrutinib. In C1 cluster (majority had no prior ibrutinb), RS and CLL samples were clearly separated into two subgroups (Figure 1b). In C2 cluster, CLL 8 treated with ibrutinib showed more similarity in gene expression to RS, than to other CLL samples treated with chemotherapy. In comparison of C2 to C1, we identified 71 differentially expressed genes, of which 34 genes were downregulated and 37 were upregulated in C2. Among the upregulated genes in C2 (majority had prior ibrutinib) are known immune modulating genes including LILRA6, FCGR3A, IL-10, CD163, CD14, IL-2RB (figure 1c). Downregulated genes in C2 are involved in B cell activation including CD40LG, CD22, CD79A, MS4A1 (CD20), and LTB, reflecting the expected biological effect of ibrutinib in reducing B cell activation. Among the 9 RS samples, we compared gene profiles between the two groups of RS with or without prior ibrutinib therapy. 38 downregulated genes and 10 upregulated genes were found in the 4 RS treated with ibrutinib in comparison with 5 RS treated with chemotherapy. The top upregulated genes in the ibrutinib-exposed group included PTHLH, S100A8, IGSF3, TERT, and PRKCB, while the downregulated genes in these samples included MS4A1, LTB and CD38 (figure 1d). In order to delineate the differences of RS vs CLL, we compared gene expression profiles between 5 RS samples and 3 CLL samples that were treated with only chemotherapy. RS samples showed significant upregulation of 129 genes and downregulation of 7 genes. Among the most significantly upregulated genes are multiple genes involved in monocyte and myeloid lineage regulation including TNFSF13, S100A9, FCN1, LGALS2, CD14, FCGR2A, SERPINA1, and LILRB3. Conclusion: Our study indicates that ibrutinib-resistant, RS-involved tissues are characterized by downregulation of genes in B cell activation, but with PRKCB and TERT upregulation. Furthermore, RS-involved nodal tissues display the increased expression of genes involved in myeloid/monocytic regulation in comparison with CLL-involved nodal tissues. These findings implicate that differential therapies for RS and CLL patients need to be adopted based on their prior therapy and gene expression signatures. Studies using large sample size will be needed to verify this hypothesis. Figure Disclosures Zhao: Merck: Current Employment. Blumenschein:Merck: Current Employment. Yearley:Merck: Current Employment. Wang:Novartis: Research Funding; Incyte: Research Funding; Innocare: Research Funding. Parikh:Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kenderian:Sunesis: Research Funding; MorphoSys: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Gilead: Research Funding; BMS: Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Juno: Research Funding; Mettaforge: Patents & Royalties; Torque: Consultancy; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding. Kay:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Ding:DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees.

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Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽

10.1182/blood-2019-128807 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3433-3433

Author(s):

Caitlin Siebenaller ◽

Madeline Waldron ◽

Kelly Gaffney ◽

Brian P. Hobbs ◽

Ran Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Smoking Status ◽

Consolidation Therapy ◽

Peripheral Vascular ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

History Of ◽

Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

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Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽

10.1182/blood-2019-130419 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4619-4619

Author(s):

Jee Yon Shin ◽

Sung-Soo Park ◽

Gi June Min ◽

Silvia Park ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Advisory Committees ◽

Sibling Donor ◽

Alternative Donor ◽

Matched Sibling ◽

Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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