Background: Liposomal daunorubicin and cytarabine (CPX-351) has shown a survival advantage for older patients (>60years) with secondary AML compared to 3 + 7 chemotherapy however in younger patients there is a lack of randomised evidence for benefit. We have previously reported improved survival with FLAG-Ida treatment as treatment intensification for younger patients identified with high risk (HR) AML following induction therapy and for patients with secondary AML (Burnett AK et al. Leukemia. 2018 Dec;32(12):2693-2697) and considered this regimen an appropriate comparator for trials in younger patients. Aims: We compared CPX-351 with FLAG-Ida in a randomised fashion in patients who were either HR at trial entry based on cytogenetics or identified as HR following induction or at relapse. Methods: The AML19 trial (ISRCTN78449203) randomised CPX-351 vs FLAG-Ida in 635 patients mainly <60 years with HR AML or MDS (>10% blasts) (median age 53.6 yrs). Three groups of HR patients were randomised 2:1 in favour of CPX with the aim of proceeding to allogeneic transplant. Group 1 (n=195) had known adverse risk cytogenetics (Grimwade et al, Blood 2010,116, 354) and were randomised at diagnosis between 4 courses of CPX-351 and 2 courses of FLAG-Ida followed by MACE/MidAC consolidation. Group 2 (n=263) were HR by validated risk score, had FLT3-ITD without an NPM1 mutation, had refractory disease and were randomised after induction course 1. Group 3 (n=177) were randomised after course 2 if they had persisting MRD at the time of relapse. Here we present results for Group 1. Group 1 was not powered to claim statistical significance; therefore, these results are intended to be exploratory and hypothesis generating. Results: Group 1 included 49.2% with de novo AML 20.3% patients with secondary AML and 30.5% with HR MDS. The Overall response rate(CR/CRi) was 64.8% for CPX-351 and 74.4% for FLAG-Ida (univariate OR:0.57, 95%CI 0.30-1.10, p=0.09). Overall survival (OS) at 3 years was 32% and 24%, median OS was 13.3 months vs 10.2 months (univariate HR:0.83, 95%CI 0.58-1.18, p=0.3) for CPX -351 and FLAG-Ida respectively (Figure 1a). Event free survival (EFS) was not significantly different (HR:0.91 95%CI: 0.50-1.64, p=0.76). Relapse free survival (RFS) at 3 years was 43% and 28%, median RFS was 22.1 months vs 14 months (univariate HR:0.66, 95%CI 0.41-1.06, p=0.09) for CPX -351 and FLAG-Ida respectively (Figure 1b). RFS was significant when adjusting for NPM1 mutation status or FLT3 mutation status using multivariable cox regression model with RFS being better with CPX-351 compared to FLAG-Ida (HR:0.58, 95% CI0.36-0.95, p=0.03). Median duration of remission favoured CPX and was 319.5 days vs 167 days (p=0.046) for CPX vs FLAG-Ida respectively. Haematological toxicity was greater in course 1 with CPX-351 with platelet recovery to 100x109/L at 34.5 days versus 29 days (p<0.001) and neutrophil recovery to 1.0x109/L at 32 days vs 30 days.(p=0.12). Day 30 and day 60 mortality were not significantly different between arms with 4.8% vs 7.3% (p=0.46) and 12.4% vs 11.0% (p=0.77) for CPX-351 and FLAG-Ida respectively.Compliance was better with CPX-351 with 90.7% vs 83.0% receiving the scheduled course 1 dose. More patients receiving CPX-351 were transplanted (50.5% vs 41.5%) with the median number of courses given prior to transplant 2 in both arms. Image:Summary/Conclusion: In patients with adverse cytogenetics CPX-351 did not improve response, OS or EFS compared to FLAG-Ida but was associated with better duration of remission and RFS. Further follow-up is needed to determine the clinical significance of those differences.

Background:Mechanisms of pain associated with joint hypermobility are poorly understood and include nociceptive pain from structural joint changes along with soft tissue injuries linked to impaired proprioception; central sensitisation associated with chronic pain and muscle weakness alongside deconditioning. Anxiety and depression are also thought to play a role in patients presenting with pain and hypermobility. We have observed an increase in the rate of orthopaedic surgical procedures undertaken in patients attending the hypermobility clinics compared to those attending the general rheumatology and chronic pain clinics. There is limited published data regarding orthopaedic interventions in patients with hypermobility related disorders especially those with confirmed genetic mutations.Objectives:We aimed to evaluate the characteristics of patients in our hypermobility cohort focusing on those who had received prior surgical intervention in order to understand the underlying mechanism behind their presentations.Methods:A retrospective review of medical records was conducted of patients attending a hypermobility clinic at our tertiary referral centre, University College London Hospital, between January 2018 and December 2018.Results:There were 350 patients (300 females, 50 males) with a mean age of 36 years (range 18-71 years). 63% had a diagnosis of Hypermobility Spectrum Disorder or Hypermobility Syndrome and 37% had a type of Ehlers-Danlos Syndromes (EDS) (hypermobile, classical, vascular or other rare type). 46 patients (13%) had documented genetic mutations. 83 patients (24%) had undergone orthopaedic interventions including 9 who had EDS with confirmed genetic mutations. 54% of patients who had surgical intervention were under the age of 40. The total number of surgical procedures in the cohort was 227 (equating to 0.6485 interventions per patient). Of those requiring operative intervention, the average number of interventions per patient was 2.73. One third of patients had surgery on two or more joint groups, including 8 patients (2%) who had surgery in four or more joint groups. Knees (24%) and hips (23%) were the most common sites for operative intervention with 9% having surgery on their shoulders. 29% of pts had significant hypermobility with a Beighton score of 7 and above but there was no correlation between Beighton score and number of surgical procedures. Only 2% of cases were referred from an orthopaedic team thereby excluding a referral bias.Conclusion:Patients with hypermobility related disorders have a significant number of orthopaedic surgical procedures on multiple sites and at a young age, with indication of mechanical pathology playing an important role in their symptoms. The Beighton score does not appear to be a reliable predictor of surgical intervention. This is not surprising given that the score only covers 5 joint areas and excludes common surgical sites such as the hips and shoulders. Early diagnosis and a holistic non-operative approach combining physiotherapy and chronic pain management is essential to reduce the need for multiple surgical procedures.References:[1]Chopra P, Tinkle B, Hamonet C, Brock I, Gompel A, Bulbena A, et al. Pain management in the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet [Internet]. 2017 [cited 2020 Jan 27];175(1):212–9. Available from:http://www.ncbi.nlm.nih.gov/pubmed/28186390[2]Shirley ED, Demaio M, Bodurtha J. Ehlers-danlos syndrome in orthopaedics: etiology, diagnosis, and treatment implications. Sports Health [Internet]. 2012 Sep [cited 2019 Jan 30];4(5):394–403. Available from:http://www.ncbi.nlm.nih.gov/pubmed/23016112Disclosure of Interests:None declared

Ehlers-Danlos Syndromes are heritable connective tissue disorders.They are multisystemic and patients can present with several symptoms such as joint pain and instability, visceral and autonomic dysfunction, as well as significant psychosocial sequela. Managing this cohort of young patients is usually challenging as many patients present late due to delayed diagnosis, often with several complications, problems with mobility and opioid use. Furthermore, there is often a prolonged lack of coordinated healthcare and access to social care services. A recent parliamentary debate in the U.K. highlighted that hEDS services are excluded from specialist Rheumatology commissioning services. In order to ascertain the relevance and utility of specialist services in this population, we conducted this study.The objective of this study was to map the patient experience following a referral to the specialist clinic in order to assess the need for an integrated, multidisciplinary approach to treating patients with hypermobility EDS.We retrospectively reviewed the records of 50 patients with the diagnosis of hypermobility EDS who were seen in a specialist hypermobility clinic at University College Hospital UCLH between January 2016 and March 2016. Relevant data was collected regarding their medical care in our hospital up to October 2019.The median age was 37 (range 21-59). We had 10 males and 40 females. The diagnosis of hypermobility EDS was based on the 1997 criteria as these patients were seen prior to the 2017 classification. Overall, the study yielded 6 key themes: 1. All patients experienced chronic pain, with 36% reporting use of opioids for pain management. 2. Patients were referred to multiple medical specialities within the same hospital trust, (22% patients were referred to ≥5 specialities). 3. Patients required a high number of follow up appointments (28% of patients required ≥20 follow-up visits). 4. Failed discharges were common; patients were often referred back to the Rheumatology Clinic despite being discharged to primary care. 5. Patients had a significant number of comorbidities, reflected by polypharmacy. (36% of patients were prescribed ≥5 medications). 6. Disability was high (20% of patients reported severe mobility problems).This study shows that patients with hEDS referred to UCLH have significant levels of disability, opioids use and polypharmacy especially for a relatively young population of patients. They need a complex interdisciplinary approach in a timely manner. In order to minimise delays and allow earlier diagnosis and intervention, we have recently adopted a multidisciplinary team approach, including pain specialists, rheumatologists, psychologists, physiotherapists, nurse specialists, urogynaecologists and neurogastroenterologists. This allows more coordinated and efficient care and incorporates an EDS-specific pain management programme. Specialised services for complex hEDS cases should be established and adequately resourced. Moreover, it would be cost effective to commission a patient-centred “one-stop-shop” service, where patients, who often travel from long distances with severe disabilities, can be seen by multiple specialities in a single visit.[1]Bennett, S., Walsh, N., Moss, T. and Palmer, S. (2019). Understanding the psychosocial impact of joint hypermobility syndrome and Ehlers–Danlos syndrome hypermobility type: a qualitative interview study. Disability and Rehabilitation, pp.1-10. Healthwatch Calderdale. (2019). Hypermobility Syndromes Project - Healthwatch Calderdale.[2]Tinkle, B., Castori, M., Berglund, B., Cohen, H., Grahame, R., Kazkaz, H. and Levy, H. (2017). Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), pp.48-69.None declared

Bioluminescent bacterial biosensors can be used in a rapid in vitro assay to predict sensitivity to commonly used chemotherapy drugs in acute myeloid leukemia (AML). The nucleoside analog cytarabine (ara-C) is the key agent for treating AML; however, up to 30 % of patients fail to respond to treatment. Screening of patient blood samples to determine drug response before commencement of treatment is needed. To achieve this aim, a self-bioluminescent reporter strain of Escherichia coli has been constructed and evaluated for use as an ara-C biosensor and an in vitro assay has been designed to predict ara-C response in clinical samples. Transposition mutagenesis was used to create a cytidine deaminase (cdd)-deficient mutant of E. coli MG1655 that responded to ara-C. The strain was transformed with the luxCDABE operon and used as a whole-cell biosensor for development an 8-h assay to determine ara-C uptake and phosphorylation by leukemic cells. Intracellular concentrations of 0.025 μmol/L phosphorylated ara-C were detected by significantly increased light output (P < 0.05) from the bacterial biosensor. Results using AML cell lines with known response to ara-C showed close correlation between the 8-h assay and a 3-day cytotoxicity test for ara-C cell killing. In retrospective tests with 24 clinical samples of bone marrow or peripheral blood, the biosensor-based assay predicted leukemic cell response to ara-C within 8 h. The biosensor-based assay may offer a predictor for evaluating the sensitivity of leukemic cells to ara-C before patients undergo chemotherapy and allow customized treatment of drug-sensitive patients with reduced ara-C dose levels. The 8-h assay monitors intracellular ara-CTP (cytosine arabinoside triphosphate) levels and, if fully validated, may be suitable for use in clinical settings.

Resistance to treatment is multi-factorial, including increased export of the parent compound from cells, insufficient conversion of Ara-C to the active metabolite Ara-CTP, and increased deamination of Ara-C to the inactive Ara-uracil (Ara-U). There is a requirement for a test to identify the extent of resistance, independent of cause, which in combination with cytogenetic screening could allowing tailoring of the dose and/or selection of combination therapy.