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A low-dose rituximab regimen for first-line treatment of acquired haemophilia A. INTRODUCTION Acquired haemophilia A (AHA) is a rare disease caused by the development of autoantibodies against FVIII. Diagnosis involves confirmation of FVIII deficiency and the presence of an inhibitor via the Bethesda assay. Severe bleeding is often managed with bypassing agents such as recombinant factor VII. This is then followed by eradication of the inhibitor with immunosuppression which typically includes a corticosteroid backbone. AIM Review the current management and outcomes of AHA in Queensland, Australia. Determine the incidence, demographics and clinical characteristics of AHA patients. METHODS Retrospective case series of AHA diagnosed between May 2014 and August 2018. Data were derived from the Australian Bleeding Disorders Registry and state-wide pathology database. Data collection proforma was completed by the treating haematologist and reviewed/compiled centrally. RESULTS 24 patients were identified (incidence 1 in 1.27 million). The median age was 76.5 years. Median follow-up was 20 months. Index bleed was atraumatic and skin/soft tissue in the majority of patients. Recombinant FVIIa was the most commonly used haemostatic therapy and effective in 85% of patients. Immunosuppression and steroid usage were uniform. Upfront second agent was used in 75% of patients and was most commonly rituximab. 87.5% of patients achieved a complete remission in a median time of 48 days. Low-dose rituximab was frequently used and equally as efficacious as standard dose. CONCLUSION Immunosuppression with combination therapy, notably rituximab, appears to be non-inferior and has a favourable side effect profile.

Introduction Plasmablastic lymphoma (PBL) is a rare, aggressive large cell lymphoma, first described in 1997. PBL is strongly associated with immunodeficient states, such as HIV infection and solid organ transplantation, but up to one third of cases are reported to occur in immunocompetent patients. The pathogenesis of PBL is incompletely understood, though the oncogenic impact of EBV, in particular in the context of dysregulated immune surveillance, together with acquired abnormalities in the MYC pathway appear to play key roles in many cases. Plasma cell markers such as CD138 and CD38 are typically positive, as well as CD30 in a significant subset. Classical B cell markers such as CD20, CD19 and PAX5 are typically absent. The literature on clinical outcomes in PBL is generally limited to small, single-centre case series. Reports describe an aggressive disease of poor prognosis, with median survival of 8 to 15 months, with one series reporting a longer median survival of 32 months. Methods We retrospectively identified patients diagnosed with PBL between 1999 and 2019 from 16 sites across Australia, the United Kingdom and Canada. Patients aged ≥18 years with confirmed tissue diagnosis of PBL at their local treating centre were included. Factors associated with overall survival (OS) were analysed using Cox regression, stratified by site to account for heterogeneity across sites. Risk time for mortality began on the date of diagnosis and ended on the date of death. Patients who were alive, lost to follow-up or transferred to another centre for care, were censored on the date of last follow-up. Risk factors analysed included age, year of diagnosis, HIV status, MYC rearrangement status, CD30 status, lactate dehydrogenase level, disease stage by Lugano consensus criteria, and bone marrow involvement. Results We identified 197 patients with PBL (Table 1). The median age at diagnosis was 55 years (range 18-95) and there was a male predominance (69%). 37% of patients were HIV positive, 56% were HIV negative and 7% were either not tested or had missing results. Other immunosuppressive risk factors included solid organ transplant, allogeneic stem cell transplant (SCT), and immunosuppressive medication. No immunodeficient state was detected in 44%. Fifty per cent of patients were stage IV at diagnosis. Fifty-four per cent were staged using PET/CT. The median follow-up time from diagnosis was 1.36 years, with the longest follow up out to 18.4 years. There were 87 deaths (44%). For patients receiving first-line treatment with curative intent, the rate of complete remission was 57% (103 of 181 patients). Most patients (53%) received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy as first line, and 27% treatment of higher intensity than CHOP. Rituximab was administered to 20% and 10% were exposed to proteasome inhibitors as part of first line therapy. Five percent of patients underwent autologous SCT in first remission, and a further 5% after first relapse or later. The median survival time was 4.8 years, with a 5-year OS of 49% and 10-year OS of 45% (figure 1). In multivariate analysis the only adverse factors associated with OS were bone marrow involvement and stage IV disease. Patients without bone marrow involvement at diagnosis had improved OS, compared to those who did (hazard ratio (HR) 0.36, 95%CI 0.18-0.72, p=0.004) (figure 2). There was an increasing trend for mortality with higher disease stages (p-trend=0.002). The median survival was 14.1 years for stage I, 10.7 years for stage II, 5.1 years for stage III and 1.2 years for stage IV. However, only stage IV disease was independently associated with inferior OS in multivariate analysis (HR 2.93, 95%CI 1.43-6.00, p=0.003) (figure 3). OS did not change depending upon year of diagnosis. Conclusion We report a multinational retrospective cohort of patients diagnosed with PBL and to our knowledge the largest single series of PBL to date. OS was longer than previously published data, particularly in patients with early-stage disease. However, patients with stage IV disease and baseline bone marrow involvement had inferior OS. HIV infection did not affect outcome. These findings suggest that baseline bone marrow biopsy and PET staging are useful prognostic tools. There is also an ongoing need for the evaluation of the predictive value of PET imaging and novel agents in PBL, especially in higher-risk disease. Disclosures Di Ciaccio: Jansen: Honoraria, Other: travel and accomodation grant. Cwynarski:Takeda: Consultancy, Other: Conference/travel support; Roche: Consultancy, Other: Conference/travel support. Burton:Celgene: Honoraria; Leeds Teaching Hospitals NHS Trust: Current Employment; Takeda: Honoraria, Other: Travel Support; BMS: Honoraria; Roche: Honoraria, Other: Travel Support. Kuruvilla:Antengene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding; Merck: Consultancy, Honoraria; Celgene Corporation: Honoraria; Amgen: Honoraria; TG Therapeutics: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb Company: Consultancy. McKay:Greater Glasgow and Clyde Health Board: Current Employment; Roche, Gilead, Takeda, Janssen: Other: For lectures etc; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Linton:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Conference/travel support; Roche: Consultancy, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hartley-Taylor: Honoraria; The Christie NHS Foundation Trust and The University of Manchester: Current Employment. Manos:Bristol-Myers Squibb: Other: Conference sponsorship. Hamad:Abbvie: Honoraria; Novartis: Honoraria.

BACKGROUND Acquired haemophilia A (AHA) is a rare acquired bleeding disorder that can present with life-threatening bleeding. AIMS To describe recent Australian use of recombinant porcine factor VIII (rpFVIII) replacement therapy as a haemostatic agent in patients with acquired haemophilia. METHODS Four patients with acquired haemophilia treated in three different institutions around Australia in the past 12 months were included in the study. Haemostatic efficacy of Obizur (Takeda) was assigned by the treating haematologist according to previously published criteria. RESULTS Six bleeds were treated with rpFVIII, three of which were initially refractory to treatment with recombinant VIIa. rpFVIII was rated efficacious in 100% of bleeds by 24 h. rpFVIII loading dose was 100 U/kg (100-120 U kg-1 ) and this increased the factor VIII level (via one-stage FVIII assay) from

An independent 85‐year‐old male was admitted to the vascular surgery department with ischaemic toes initially attributed to atheroembolism in the setting of a known abdominal aortic aneurysm. His right great toe was amputated and he was discharged home with clopidogrel and aspirin. However, he re‐presented with a decline in mobility and painful digits. Examination revealed marked acrocyanosis of all his digits (left)

Summary Reasons for performing study: There is limited information about factors regulating glucose utilisation post exercise in horses. Objectives: To determine the effects of a single bout of moderate intensity exercise on measures of insulin-mediated (IMGU) and noninsulin-mediated (NIMGU) glucose uptake during a hyperglycaemic clamp (HC). Methods: Hyperglycaemic clamps were administered in random order to 8 Standardbreds under 4 conditions: 1) rest, insulinopenia (R-L); 2) rest, hyperinsulinaemia (R-H); 3) post exercise (45 min at ∼50% VO2peak), insulinopenia (Ex-L) and 4) post exercise, hyperinsulinaemia (Ex-H). In the R-L and Ex-L trials, somatostatin was infused to suppress insulin secretion and induce insulinopenia. After 30 min, a 2 h HC was initiated with plasma glucose concentrations maintained at ∼10 mmol/l by variable glucose infusion. In R-H and Ex-H, regular insulin (1.0 mu/kg bwt/min) was also administered to induce physiological hyperinsulinaemia. Serum insulin and C-peptide concentrations were measured in samples obtained at 10 min intervals. Glucose uptake was calculated from mean glucose infusion rate (GIR) during the last 60 min of the HC. Results: In all HCs C-peptide remained below baseline concentrations, evidence of suppression of insulin secretion by somatostatin. Overall, mean ± s.e. insulin concentrations during the final 60 min of the HC in R-L and Ex-L were 5.7 ± 1.1 and 6.9 ± 1.9 mu/l respectively, and corresponding values in R-H and Ex-H were 64.1 ± 11.1 and 61.2 ± 10.9 mu/l. Prior exercise affected IMGU but not NIMGU. Over the final 60 min of the HC, mean GIR was higher (P

Summary Reasons for performing study: Starch rich (S) feeds reduce insulin sensitivity in untrained horses when compared to high fat (F) feeds, but insulin sensitivity is not affected when S or F are fed during exercise training. The effects of S vs. F on training-associated alterations in skeletal muscle glucose metabolism are unknown. Objectives: To determine the effects of dietary energy source on training-associated changes in insulin sensitivity, skeletal muscle GLUT4 protein and hexokinase (HK) and glycogen synthase (GS) activities in horses. Methods: After a baseline period on an all forage diet (Phase 1), horses were adapted to high starch (S) or high fat (F) diets (n = 7/group) for 6 weeks (Phase 2) and then completed 7 weeks of exercise training (Phase 3) on the same diets. To measure insulin sensitivity (SI), minimal model analysis of a frequently-sampled i.v. glucose tolerance test was performed at the end of each phase. Middle gluteal muscle biopsies to measure GLUT-4 protein content, muscle glycogen and HK and GS activities were taken before and after euglycaemic-hyperinsulinaemic clamps administered after each phase. Data were analysed by repeated measures ANOVA. Results: In S, SI was 36% lower (P 0.05) between diets. Middle gluteal muscle GLUT-4 protein and post clamp HK activity were increased (P

Summary Reasons for performing study: No studies in horses have examined the effect of route of carbohydrate (glucose) administration on the rate of muscle glycogen storage following glycogen-depleting exercise. Hypothesis: Glucose delivery from the gastrointestinal tract limits the rate of muscle glycogen storage following glycogen-depleting exercise. Methods: In a crossover design, 7 fit horses completed treadmill exercise (EX) on 3 occasions to deplete muscle glycogen by approximately 50%. After EX horses received: 1) i.v. glucose infusion (IV; 0.5 g/kg bwt/h for 6 h), 2) oral glucose boluses (OR; 1 g/kg bwt at 0, 2 and 4 h post EX) or 3) no glucose supplementation (CON). Blood samples for measurement of glucose and insulin concentrations were collected before EX and during the 6 h treatment period. Muscle biopsies for measurement of muscle glycogen content (GLY) and glycogen synthase (GS) activity were taken before and after exercise and at 3 and 6 h. Results: Mean plasma glucose concentrations were significantly higher in IV and OR than in CON throughout treatment. The average serum insulin responses in IV and OR treatments were also significantly greater than in CON. After EX, GLY was not different among the 3 treatments. However, glycogen storage rates were significantly higher in IV than in CON and OR during the first 3 h and second 3 h of recovery, and GLY was significantly higher in IV than in OR and CON at 6 h of recovery. GS activity was significantly higher in IV than in OR and CON at 3 h of recovery. Conclusions: Muscle glycogen storage in horses during a 6 h period after exercise was enhanced by i.v. glucose administration (3 g/kg) but not by an equivalent glucose dose administered per os. While oral administration of glucose achieved a level of hyperglycaemia and hyperinsulinaemia that markedly accelerates glycogen storage in other species, the rate of glycogen storage following oral supplementation was not different to control conditions. Potential relevance: Glucose supplementation via the i.v. route should be considered when rapid replenishment of muscle glycogen stores is desired.

Summary Reasons for performing study: Increased insulin sensitivity occurs after a period of exercise training, but the mechanisms underlying this training-associated increase in insulin action have not been investigated. Objective: To examine the effects of short-term endurance training (7 consecutive days) and a subsequent period of inactivity (5 days) on whole body insulin sensitivity and GLUT-4 protein and the activities of glycogen synthase (GS) and hexokinase (HK) in skeletal muscle. It was hypothesised that training would increase insulin sensitivity in association with increased GLUT-4 protein and activities of GS and HK, but that these changes would be transient, returning to baseline after 5 days of inactivity. Methods: Seven mature Standardbred horses completed training consisting of 7 consecutive days of 45 min of treadmill exercise at a speed that elicited 55% of pretraining maximal aerobic capacity (VO2peak). Insulin sensitivity was determined by rate of glucose disposal (M) during the last 60 min of a 120 min euglycaemic-hyperinsulinaemic clamp (EHC) performed before (-2 days) and at 1 and 6 days following training. VO2peak was measured before (UT) and after (TR) training and the period of inactivity (IA). Results: Training resulted in a 9% increase in mean VO2peak (P

There is limited information about factors regulating glucose utilisation post exercise in horses.To determine the effects of a single bout of moderate intensity exercise on measures of insulin-mediated (IMGU) and noninsulin-mediated (NIMGU) glucose uptake during a hyperglycaemic clamp (HC).Hyperglycaemic clamps were administered in random order to 8 Standardbreds under 4 conditions: 1) rest, insulinopenia (R-L); 2) rest, hyperinsulinaemia (R-H); 3) post exercise (45 min at ∼ 50% VO2peak), insulinopenia (Ex-L) and 4) post exercise, hyperinsulinaemia (Ex-H). In the R-L and Ex-L trials, somatostatin was infused to suppress insulin secretion and induce insulinopenia. After 30 min, a 2 h HC was initiated with plasma glucose concentrations maintained at ∼ 10 mmol/l by variable glucose infusion. In R-H and Ex-H, regular insulin (1.0 mu/kg bwt/min) was also administered to induce physiological hyperinsulinaemia. Serum insulin and C-peptide concentrations were measured in samples obtained at 10 min intervals. Glucose uptake was calculated from mean glucose infusion rate (GIR) during the last 60 min of the HC.In all HCs C-peptide remained below baseline concentrations, evidence of suppression of insulin secretion by somatostatin. Overall, mean ± s.e. insulin concentrations during the final 60 min of the HC in R-L and Ex-L were 5.7 ± 1.1 and 6.9 ± 1.9 mu/l respectively, and corresponding values in R-H and Ex-H were 64.1 ± 11.1 and 61.2 ± 10.9 mu/l. Prior exercise affected IMGU but not NIMGU. Over the final 60 min of the HC, mean GIR was higher (P0.001) in Ex-H (5.6 ± 1.1 mg/kg bwt/min) than in R-H (3.3 ± 0.9 mg/kg bwt/min), whereas mean GIR did not differ (P = 0.26) between R-L (1.2 ± 0.3 mg/kg bwt/min) and Ex-L (1.8 ± 0.5 mg/kg bwt/min).A single bout of moderate intensity exercise increased glucose uptake during a hyperglycaemic clamp under hyperinsulinaemic conditions but not under somatostatin-induced insulinopenia.

This thesis investigated (1) effects of short term training (STT) and detraining on insulin sensitivity (SI), expression of GLUT-4 and activities of glycogen synthase (GS) and hexokinase (HK) in equine skeletal muscle and (2) effect of dietary non-structural carbohydrate (NSC) content and physical conditioning on these measurements. STT resulted in increased whole body SI, GLUT-4 protein content and GS activity in skeletal muscle. Enhancements in SI, GLUT-4 protein and GS activity were still evident after detraining. Adaptation to a high NSC diet was associated with development of a compensated insulin resistance that was partially mitigated by physical conditioning. Increased GLUT-4 protein expression and GS and HK activity may have contributed to this improvement in SI. Results demonstrated physical conditioning may attenuate changes in SI resulting from a high NSC diet by improved glucose transport and increased GS and HK activity, and that STT improvements in SI, GLUT-4 protein content and GS activity are still evident following 5 days inactivity.