Monday 20th April 2015 Free Communication Transfusion Medicine and Nursing 1 National comparative audit of patient information and consent for transfusion 2014: comparison of practice between clinical specialities S Allard1, J Grant-Casey2, E Court3, M Browett4, A Davidson5, D Watson6, D Lowe7, H Busby4, J Robinson (patient representative)1 1 NHS Blood & Transplant, London, UK; 2NHS Blood & Transplant, Oxford, UK; 3North Bristol NHS Trust, Bristol, UK; 4University of Leicester, Leicester, UK; 5NHS Blood & Transplant, Leeds, UK; 6Scottish National Blood Transfusion Service, Glasgow, UK; 7Royal College of Physicians, London, UK We conducted a National Comparative Audit of patient information & consent for transfusion in 2014 with164 NHS centres contributing data on 2784 patients. Case notes were audited to assess if the indication for transfusion was documented, if consent had been obtained and if the patient had been given written information about blood Table 1. Audit of case note documentation showed the following results

Indication for transfusion documented Consent for transfusion documented Documentation that written information given Documentation that risks explained to patient

Medical (n = 1172)

Surgical (n = 916)

Haem/onc (n = 570)













Table 2. The findings of patient recall based on completed questionnaires from 2137 patients (medical n = 874: surgical n = 745; haematology/oncology n = 518)

Patient recalls benefits being explained Recalls giving consent for transfusion Recalls being given written information Recalls risks being explained Recalls alternatives discussed

Medical (n = 874)

Surgical (n = 745)

Haem/onc (n = 518)










32% 6%

34% 6%

51% 8%

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transfusion. Patients were invited to complete a questionnaire asking them to recall if they had been asked to consent to transfusion and if they had been given written information. We have now undertaken a comparison of practice in medical (n = 1172), surgical (n = 916) and haematology/oncology (n = 570) patients which represents 95% of patients audited. The audit shows some discrepancies between patient recall and documented aspects of care but overall highlights the need for hospitals to review systems for improving their practice in relation to obtaining valid consent in all disciplines whether in the medical or surgical setting. Innovative methods of providing information to patients in addition/alternative to written information should be explored including greater use of Information Technology.

2 Excellent outcome for adults and older adolsecents following reduced intensity allogeneic haematopoietic stem cell transplantation for inherited primary immune deficiencies (PID) EC Morris1,2,3, R Chakraverty1,4,5, S Burns1,2, S Grace4, A Worth6, A Fielding4,5, S Mackinnon4,5, K Thomson3, K Peggs3,5, V Grandage3, S Denovan4, K Roberts3, S Workman2, A Symes2, M Campbell2, M Collin7, R Chee2, C Murray2, H Gaspar6, R Hough3 1 UCL Institute of Immunity and Transplantation, UK; 2 Department of Clinical Immunology, Royal Free London, UK; 3Department of Clinical Haematology, UCLH, UK; 4 Department of Clinical Haematology, Royal Free London, UK; 5UCL Cancer Institute, UK; 6Department of Immunology, Great Ormond Street Hospital, UK Introduction: PID BMT in adults previously avoided due to severe TRM/poor outcome. Methods: This study reports the outcome of 26 consecutive patients treated with reduced intensity allogeneic haematopoietic stem cell transplantation (RI Allo HSCT) for inherited primary immune deficiencies at a single centre. A total of 26 patients (21 males, five females), with a median age of 22 years (range 14–34) were transplanted. Nineteen were ≥18 years at transplant. Underlying diagnoses were X-linked CGD (n = 12), CVID (n = 3), JIA (n = 2), Autoimmune LPD (one with Fas mutation) (n = 2), variant CGD with early onset severe Crohn’s disease (n = 1), DCML Deficiency (one with Gata2 mutation) (n = 2), Common gamma Chain SCID (n = 1), Undefined SCID (n = 1), NK deficiency with IgA subclass deficiency and seronegative arthritis (n = 1), and IL12 receptor beta deficiency with recurrent salmonella sepsis (n = 1). Most patients received stems cells from matched or mismatched unrelated donors (MUD n = 11, 1Ag MMUD n = 5), 9 from matched sibling donors (Sib n = 9) and one a 10/10 paternal donor. Stem cell source was BM (n = 8) or mobilized PBSC (n = 18). RI conditioning regimens were Fludarabine, Melphalan, Alemtuzumab (n = 16), Fludarabine, Bulsulphan, Alemtuzumab (n = 6) or Fludarabine, Busulphan, ATG

doi: 10.1111/bjh.13350

Free Communication: Transfusion Medicine and Nursing (n = 4). All patients were treated in hepa-filtered single rooms and received anti-microbial prophylaxis, anti-fungal prophylaxis and CMV surveillance together with standard supportive care. Blood was assayed for chimerism by PCR analysis of minisatellite regions. Results: With a median follow up of 2 years 4 months (range 7 days to 9 years 6 months), the estimated overall survival is an excellent 79% (95% CI: 57–99%), with no deaths observed beyond 26 months. A total of 22 patients are alive. All four deaths observed have been due to transplant-related toxicity (two sepsis with multiorgan failure, 1 pulmonary toxoplasmosis and 1 severe refractory chronic extensive GVHD). Lineage specific chimerism and immune reconstitution studies have been analysed on all patients.

3 Haemostatic changes, transfusion management and clinical outcomes of obstetric massive transfusion cases in the UK LG Green1, MK Knight2, FMS Seeney3, PWC Collins4, REC Collis5, CLH Hopkinson3, AW Weeks6, NS Simpson7, SJS Stanworth8 1 Barts Health NHS Trust & NHS Blood and Transplant, London, UK; 2National Perinatal Epidemiology Unit, University of Oxford, UK; 3Statistics and Clinical Studies, NHS Blood and Transplant, Bristol, UK; 4Arthur Bloom Haemophilia Centre, Cardiff University, UK; 5Department of Anaesthetics, Cardiff and Vale University Health Board, UK; 6 Department of Women’s and Children’s Health, University of Liverpool, UK; 7Department of Women’s and Children’s University of Leeds, UK; 8NHS Blood and Transplant, Oxford & Oxford University Hospitals NHS Trust, UK Major-obstetric-haemorrhage (MT) is a major cause of guidelines recommend one MOH causes, depending on


red-blood-cell (RBC) units transfused. Understanding its coagulopathy is fundamental to improving transfusion management and its outcome. This study aimed to describe the coagulation abnormalities, transfusion management and clinical outcomes of women who developed MOH and receive ≥8 units of RBC within 24 hours of delivery. Cases were identified from all UK hospitals with obstetrician-led maternity units, using the UK-Obstetric-Surveillance-System, between July 2012 and June 2013. We identified 181 cases making the estimated incidence of MT during MOH 2.3 per 10,000 maternities. The median (IQR) age and estimated blood loss were 33 years (29–36) and 6L (4.5–8) respectively. Causes of MOH and their coagulation results are given in the table. The median (IQR) units of RBC, fresh-frozen-plasma (FFP) and cryoprecipitate transfused were: 10 (8–14), 6 (4–8), and 2 (2–4) respectively. FFP, cryoprecipitate and platelets were transfused in 99%, 77% and 61% of women respectively. 45% of women underwent hysterectomy, two died, 82% were admitted to ITU/HDU, and 28% developed additional major morbidities. Conclusion: MT due to MOH is associated with high rates of hysterectomy and morbidity. The coagulation changes during MOH differ significantly depending on its cause, indicating that we need more targeted transfusion strategies instead of the one universal strategy recommended by current guidelines. Further research should focus on how best to target/correct these coagulopathies.

(MOH) leading to massive-transfusion maternal morbidity/mortality. Current universal transfusion strategy for all clotting test results and/or number of

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

*At diagnosis of MOH.

Median (IQR) n HB (g/l) at diagnosis worst value Platelet at diagnosis count worst value (9109/l) 1000 9 109/ l) with essential thrombocythaemia (ET) across 13 European countries between 2005 and 2009. Patients were followed for 5 years. The primary objective was safety and pregnancy outcomes of anagrelide (ANA) compared with other cytoreductive therapies (CRTs). Secondary objectives included efficacy, measured by incidence of thrombohaemorrhagic events and platelet reduction. Event rates are presented as number of patients per 100 patient years exposure and by treatment at time of event. 3649 patients were categorised according to treatment at registration: ANA (n = 804), ANA+other CRT (n = 141), other CRT (n = 2666) and no CRT (n = 38). Median age was lower in the ANA (55.5 years) versus other CRT group (70.0 years). Thrombohaemorrhagic and malignancy event rates are displayed in Table 1. 105 patients transformed to myelofibrosis (MF) and 62 to acute leukaemia (AL). In patients who had only ever received either ANA or hydroxycarbamide (HC), the rate of transformation to MF was higher in the ANA versus HC group (0.78 versus 0.17) whereas transformation to AL was higher in the HC versus ANA group (0.22 versus 0). No unexpected side effects were noted. Patients who received ANA were younger than those who received other CRT. The thrombohaemorrhagic event rates were generally low, with differences in venous thrombotic and haemorrhagic event rates between the ANA+other CRT group. Transformation to MF was more frequent in the ANA group while transformation to AL was more common in the other CRT group.

ANA N = 1127

Other CRT N = 2909

ANA+other CRT N = 451

No CRT N = 645

2.75 1.63 0.35 0.87

2.60 1.62 0.57 0.49

2.86 2.25 0.11 0.69

4.91 2.74 1.13 1.12

1.31 0.17 0.49

0.32 0.33 1.35

1.27 0.46 0.46

2.31 2.57 1.95

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104


Free Communication: Myeloid Malignancies

12 Immunological profile of patients after HSCT using the FCC conditioning regimen for treatment of severe aplastic anemia indicates potential basis for tolerance with mixed T-cell chimerism and extremely low incidence of GvHD

13 Donor lymphocyte infusion – a retrospective single centre audit

F Grimaldi2, R Grain1, P Perez-Abellan1,2, S Best2, N Lea2, JP Veluchamy1, M Atif1, A Kulasekararaj1,2, A Pagliuca1,2, V Potter2, GJ Mufti1,2, JC Marsh1,2, LD Barber1 1 Department of Haematological Medicine, King’s College London, UK; 2Department of Haematology, King’s College Hospital, NHS Foundation Trust, London, UK

Donor lymphocyte infusion (DLI) is used either to treat [therapeutic DLI(tDLI)] relapsed haematological malignancies after haematopoietic stem cell transplant (HSCT), or pre-emptively[pre-emptive DLI (pDLI)] in cases of mixed donor chimerism (MDC) with a view to achieving full donor chimerism (FDC). For the purpose of this audit, FDC was defined as >95% CD3 chimerism. Data on patients who received DLI after T-cell depleted HSCT at King’s College Hospital, London, between 2001 and 2013 was reviewed. 241 patients (male:151; myeloid malignancy:81%, lymphoid malignancy: 18%) received total 581 DLI doses. 126 patients received 294 doses of pDLI (median: three doses; range: 1–8) and 106 patients received 262 doses of tDLI (median:3 doses; range: 1–8). In 9 patients indication was unknown. Median time from HSCT to 1st pDLI dose was 196 days (range: 85 to 36271 days) and that between pDLI doses was 70 days (range: 10 to 2723 days).In this group, median 1st pDLI dose received was 5 9 105 CD3+/kg (range: 1 9 105 to 7 9 107 CD3+/kg) and median cumulative dose was 1.5 9 106 CD3+/kg (range: 1 9 105 to 3 9 108 CD3+/kg). Median time from HSCT to 1st tDLI dose was 372 days (range: 76–3425 days) and median time between tDLI doses was 57 days (range: 7–947 days). Median 1st tDLI dose was 1 9 106 CD3+/kg (range: 1 9 103 to 5 9 108 CD+/kg) and median cumulative tDLI dose was 1.1 9 107 CD3+/kg (range: 5 9 105 to 6 9 108). 144 months following first pDLI dose, overall survival was 70% (event free survival [EFS]: 60%) in those who achieved FDC versus 35% (EFS: 35%) who remained with MDC (Figure1). Fig. 1 EPS (A) and OS (B) based on chimorism status after pDU Use of DLI to treat haematological malignancies, more frequently myeloid malignancies, in post HSCT setting is common in our institution. Good outcomes are demonstrated for patients receiving pDLI. A large prospective randomised trial is needed to establish efficacy, toxicity and ideal approach of its use.

We previously reported the HSCT conditioning regimen for severe aplastic anemia (SAA) using fludarabine, cyclophosphamide and alemtuzumab (FCC) is associated with low GvHD risk and excellent overall survival (OS). Mixed T-cell chimerism is frequent and persists despite discontinuation of immunosuppression. We propose alemtuzumab facilitates tolerance and hence low GvHD risk. To investigate, the lymphocyte composition of 37 adult patients transplanted for SAA (11 sibling, 26 VUD) was assessed. Excellent clinical outcomes were confirmed with 94% OS and low GvHD rates (acute 17% all grade I-II, chronic 14% only 1 severe). Comparison of lymphocyte composition to 11 healthy age-matched individuals showed profound and prolonged lymphopenia. NK cells recovered first, but numbers remained below normal. T cells comprised only 2.6% of lymphocytes at day 30, rising to 41% by day 360 but still significantly below normal (66%, p = 0.018). Deficiency was greatest for CD4+ T cells, but proportion of regulatory T cells (CD4+ CD25high CD27+ FoxP3+) within this population was normal (range 4.2–7.4% compared to 5.3%). B cell recovery was notably robust, with normal numbers by day 100. Proportion of immature transitional B cells (CD24+ CD38+, CD27-, IgM high IgD high) were significantly increased early after HSCT (p = 0.003 at day 90). This subset is known to possess immune suppressive activity. Patients aged 600 centres (~60% UK and 40% non UK). The sample containing no rivaroxaban had normal PT and APTT as expected.PT results: 29 ng/ml – all reagent medians normal or near normal; 121 ng/ml all medians prolonged and ranged from 1.25–1.81; 346 ng/ml – range 1.50-2.97; 734 ng/ml – range 2.07– 5.45. APTT results: 29 ng/ml – both normal and abnormal medians occurred – range 1.08–1.33; 121 ng/ml – all prolonged, range 1.33– 1.67; 346 ng/ml – range 1.63-2.10; 734 ng/ml – range 2.16–2.94. A concentration of 121 ng/ml (below average expected peak levels) prolonged the PT and APTT with all reagents. Prolongation of APTT and especially PT by higher rivaroxaban concentrations varied markedly between reagents so interpretation of PT and APTT results in the presence of rivaroxaban must take account of the reagents used.

LA detection and of aPL on rivaroxaban anticoagulant action. Rivaroxaban and 52 IgG preparations (20 LA positive, 12 LA negative thrombotic antiphospholipid syndrome [APS] patients, and 20 normal controls [NC]), were spiked into pooled normal plasma (PNP) for LA testing. In addition, aPL effects on rivaroxaban anticoagulant action were assessed using a thrombin generation (TG) test, by calibrated automated thrombography, and anti-Xa levels. LA detection was also studied in thrombotic APS patients receiving rivaroxaban 20 mg once daily on samples taken at peak and trough levels of rivaroxaban. In vitro spiking of samples with rivaroxaban showed no false positive LA with Textarin time, Taipan venom time/Ecarin clotting time (TVT/ECT), dilute prothrombin time (dPT) and in-house dilute Russell viper venom time (DRVVT); but false positives in the majority of NC and LA negative IgG (18/20 [90%] and 11/12 [92%] respectively) with two commercial DRVVT reagents, at 250 ng/ml but not 50 ng/ml rivaroxaban (expected peak and trough levels respectively). Ex vivo studies: six LA positive patients on rivaroxaban remained LA positive with TVT/ECT and both DRVVT reagents, at peak (162–278 ng/ml) and trough (30–85 ng/ml) rivaroxaban levels. Six LA negative patients became (apparently) LA positive with both DRVVT reagents, test/confirm ratio median [CI]: 1.6 [1.3–1.8], 1.6 [1.4–1.9], but not by TVT/ECT (1.1 [0.8–1.2]) at peak rivaroxaban levels; and remained LA negative with both DRVVT reagents and TVT/ECT at trough levels. aPL positive IgG spiking of PNP had no effect on rivaroxaban anticoagulant effects on thrombin generation or rivaroxaban anti-Xa levels. In conclusion, the TVT/ECT ratio and Textarin time were not affected even at peak rivaroxaban levels, enabling detection of LA ex vivo. aPL had no effects on rivaroxaban anticoagulant action in vitro.

18 Idarucizumab, a specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in elderly and renally impaired subjects

D Jayakody Arachchillage1, I Mackie1, M Efthymiou1, D Isenberg3, S Machin1, H Cohen1,2 1 Haemostasis Research Unit, Department of Haematology, University College London, UK; 2Department of Haematology, University College London Hospitals NHS Foundation Trust, UK; 3Centre for Rheumatology, University College London Division of Medicine, UK

S Austin1, S Glund2, J Stangier3, M Schmohl3, V Moschetti2, W Haazen4, M De Smet5, D Gansser3, S Norris6, B Lang7, P Reilly6 1 Department of Haematology, St George’s Healthcare NHS Trust, London, UK; 2Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 3Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 4Clinical Pharmacology Unit, SGS Life Science Services, Antwerp, Belgium; 5Clinical Operations, SCS Boehringer Ingelheim Comm. V., Brussels, Belgium; 6Boehringer Ingelheim Pharmaceutical Inc., Ridgefield, CT, USA; 7Clinical Biostatistics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

Rivaroxaban can affect lupus anticoagulant (LA) testing, and antiphospholipid antibodies (aPL) may interfere with rivaroxaban anticoagulant action. We investigated the influence of rivaroxaban on

Dabigatran is an oral anticoagulant for stroke prevention in atrial fibrillation, and treatment and secondary prevention of deep vein thrombosis and pulmonary embolism. All anticoagulants are

17 Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome


ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Free Communication: Haemostasis and Thrombosis associated with an increased risk of bleeding. Bleed management can be achieved through established therapies; however the availability of an antidote to dabigatran could further facilitate the management of patients with anticoagulant-related bleeding or requiring emergency invasive procedures. Idarucizumab is a humanized antibody fragment being investigated as a specific antidote for the anticoagulant effect of dabigatran. Pre-clinical studies indicate idarucizumab binds specifically to and inhibits dabigatran-induced anticoagulation. In the present study, the safety, tolerability, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in a double-blind, placebo controlled cross-over study of 46 male and female volunteers. Dabigatran 220 mg bid in healthy subjects and 150 mg bid in subjects with mild or moderate renal impairment was given over 4 days to achieve steady state conditions. Idarucizumab doses of 1– 5 g were given i.v. 2 h after the last dose of dabigatran. The anticoagulant effect of dabigatran and its reversal was assessed by coagulation time measurements (diluted Thrombin Time, Ecarin Clotting Time and activated Partial Thromboplastin Time). All administered doses of idarucizumab were safe and well tolerated. Prolongation of clotting times across all assays was reversed to baseline at the end of the 5 minute i.v. idarucizumab infusion. The administration of 5 g or 2 9 2.5 g led to sustained reversal of dabigatran-induced anticoagulation in subjects of different age groups and renal function. Also a second administration of idarucizumab (2 months after the first) was safe and resulted in complete reversal. Effective dabigatran anticoagulation could be re-established 24 h after idarucizumab infusion. These results support the use of total dose of 5 g idarucizumab as an effective, safe and well tolerated dabigatran reversal agent for further clinical study.

19 Whole genome sequencing and inherited diseases of the blood stem cell and its progeny S Papadia, on behalf of the NIHR BioResource – Rare Diseases and BRIDGE projects Department of Haematology, University of Cambridge, Cambridge, UK Next-Generation Sequencing Techniques is providing a progressively accurate catalogue of human genetic variation. Since 2009, tens of thousands of exomes have been sequenced, from patients with a variety of diseases and controls. With sequencing becoming increasingly more affordable Whole Genome Sequencing (WGS) has become available for patients with Rare Diseases of unexplained molecular aetiology. The NIHR BioResource – Rare Diseases works in partnership with Genomics England Ltd (GEL) to deliver the 100,000 Genomes project. In parallel to the GEL pilot for Rare Diseases we initiated 12 BRIDGE projects, three of which are related to rare diseases of blood. These three projects enrol well-characterised patients with Primary Immune Disorders, Stem Cell and Myeloid Disorders and Bleeding and Platelet Disorders (BPD) and ~1600 probands have been enrolled to date. Patients are consented using a generic Rare Diseases participant information leaflet and consent form, and clinical and laboratory data are recorded in a database. For the BPD project ~1000 patients have been recruited so far from 16 centres and recruitment is ongoing, with more UK Haemophilia centres becoming active members of the consortium. The results are analysed by a multi-disciplinary team of haematologists, study coordinator, bioinformaticians and experts in statistical genomics. Using an approach of data sharing between hospitals we have identified NBEAL2 and RBM8A as the causative genes for Grey Platelet Syndrome and Thrombocytopenia with Absent Radii,

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

respectively. Additionally we discovered another five novel BPD genes and observed replication of the recently-discovered BPD genes ACTN1, GFI1B and RASGRP2. We demonstrate the feasibility of WGS in the clinical setting, in appropriately consented participants. This in conjunction with detailed phenotyping leads to an increased understanding of the critical genes that regulate megakaryopoiesis and haemostasis. The results are used to develop affordable DNA-based tests to reduce the diagnostic delay for patients with rare inherited blood diseases.

20 Oral anticoagulant agent-associated bleeding events reporting system (ORANGE) study L Green1,2,3, J Morris1, R Alikhan4, N Curry5, R Maclean6, K Saja7, S Stanworth3,5, C Tait8, J Tan1, P MacCallum1,2 1 Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK; 2Barts Health NHS Trust, London, UK; 3NHS Blood and Transplant, UK; 4 University Hospital of Wales, Cardiff and Vale University Health Board, Wales, UK; 5Oxford University Hospitals NHS Trust, UK; 6Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK; 7Barking, Havering and Redbridge University Hospitals NHS Trust, London, UK; 8Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, UK Major bleeding is a recognised complication of oral-anticoagulant (OAC) therapy, but there is little information on the frequency and types of bleeds. The aim of this prospective, ongoing observational study is to describe the management and clinical outcomes of patients who develop major bleeding associated with warfarin and new OACs (NOACs) in the UK. Standardised pre-piloted data collection forms were used to record baseline and outcome data, and treatment. Between October 2013 and June 2014, 371 cases (181 male, 190 female) were reported by 15 hospitals; median [min-max] age was 78 [23–98] years. These consisted of 340, 22, 7 and 2 events associated with warfarin, rivaroxaban, dabigatran and apixaban respectively. 11% of patients were also on one or more antiplatelet therapy and 13% have had at least one previous major bleed. Intracranial-haemorrhage (ICH), gastro-intestinal (GI) bleeds, and all other bleeds made up 43% (19%), 33% (52%) and 24% (29%) of warfarin (NOAC) cases respectively. For warfarin cases, 78%, 82% and 41% received vitamin K, prothrombin-complex-concentrate (PCC) and blood transfusion (includes any blood components) respectively. For NOACs, 29%, 26% and 52% received tranexamic acid, PCC/Factor-Eight-Inhibitor-Bypassing-Agent, and blood transfusion respectively. At 30 days, 74.4% of patients were discharged [mean (min-max) stay in hospital: 9.6 (0–29) days}; 9.3% were still inpatient; and 16.3% died (16.2% and 16.7% of warfarin and NOACs cases respectively), with 68% of deaths having presented initially with ICH. 22% of the total also developed one or more major morbidities. In summary the high 16% mortality rate at 30 days was similar for both warfarin and NOACs. This is surprising given that ICH bleeds were the most frequent type of bleed with warfarin (43%) and GI bleeds with NOACs (52%). These are preliminary results and more cases are being collected in order to evaluate the clinical outcomes in greater detail.


Free Communication: Haemostasis and Thrombosis

21 The FVIII:C to VWF:Ag ratio in patients with von Willebrand disease type I may indicate co-inheritance of F8 or VWF 2N variants

AL Knott1, C Pateman1, E Franklin1, C Reilly-Stitt1, A Mumford2 1 Bristol Haemophilia Comprehensive Care Centre, University Hospitals Bristol NHS Foundation Trust, UK; 2School of Cellular and Molecular Medicine, University of Bristol, UK Diagnosis of type I von Willebrand disease (VWD-I) requires demonstration of concordantly reduced plasma von Willebrand factor (VWF) activity and antigen (VWF:Ag) in patients with abnormal bleeding. Reduced plasma FVIII activity (FVIII:C) may be a feature of VWD-I, but also of other disorders such as haemophilia A (HA) and VWD Normandy subtype (VWD-2N). In the previous literature we identified 10 cases with VWD-I co-inherited with VWD-2N and 5 male cases with VWD-I co-inherited with HA. These cases displayed reduced FVIII:C (0.01-0.28 IU.mL) and reduced FVIII:C to VWF:Ag ratios (0.02–0.67). We reviewed 167 cases registered at our Centre with VWD-I or low von Willebrand factor defined according to recently recommended diagnostic criteria (VWF Ricof activity (VWF:RCo) 0.6). The median FVIII:C in this group was 0.55 IU/ml (range 0.09–1.3) and median FVIII:C to VWF:Ag ratio 1.57 (range 0.33-3.5). 20/167 (12%) of these cases had a FVIII:C to VWF:Ag ratio of ≤1. Of the 7 index cases in this group who have to date undergone complete genetic analysis of F8 or the 2N VWF region, there was 1 male with F8 p.Ser700Leu, 1 male with F8 c.219C>T and 1 female carrier of F8 p.Arg2178His, all previously associated with mild HA. 1 case harboured a heterozygous VWF p.Arg1250His which has previously associated with a VWF-2N phenotype. The 3 remaining cases did not have demonstrable HA or VWD-2N variants. These data suggest that the additional diagnoses of HA or VWD-2N should be considered in patients with VWF parameters indicating VWD-I or low VWF and who have a reduced FVIII:C to VWF:Ag ratio. Identification of co-inherited bleeding disorders in patients with VWD has important implications for genetic counselling and treatment.


22 ThromboGenomics: next generation sequencing to diagnose inherited bleeding, thrombotic and platelet disorders I Simeoni, on behalf of the ThromboGenomics Consortium Department of Haematology, University of Cambridge, Cambridge, UK According to the UK National Haemophilia Centre Database for inherited bleeding and platelet disorders (BPDs), >20% of patients affected by these disorders do not receive a definitive molecular diagnosis. These cases include platelet function defects and unclassified bleeding and thrombotic disorders, for which the current laboratory tests are not sufficient to establish the molecular causes. The ThromboGenomics project aims to overcome this unmet medical need by making available a next-generation sequencing (NGS) based test. A ROCHE NimbleGen 1 Mb sequence capture platform has been developed and validated to screen in parallel 69 genes known to be causative of BPDs. So far 297 samples from 18 centres in Europe and the USA have been enrolled and sequenced. The sequencing of pools of 24 DNA samples on a single Illumina HiSeq lane resulted in 99.2% coverage of the 1 Mb target region at a read depth of 50 fold. Expected mutations have been confirmed in 133 out of 135 samples submitted with known BPD mutations. To unequivocally predict the consequence of the genomic DNA variants, gene experts have contributed to the project by annotating the gene sequence and relevant transcript(s) to clinical reference standards. The selected reference sequences have been submitted to the publically accessible Locus Reference Genomic (LRG) database for use by the global clinical pathology community in the generation of clinical reports. In conclusion the ThromboGenomics project has delivered the clinical validation of an affordable NGS platform which can be used to make a real impact on the clinical care of patients and their close relatives with rare inherited BPDs. To engender the use of this comprehensive DNA test in the NHS, samples from clinically well-characterised patients can be submitted for analysis and results will be returned after review by the ThromboGenomics multi-disciplinary reporting team.

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Free Communication: Paediatrics

Free Communication Paediatrics 23 Iron status in paediatric acute lymphoblastic leukaemia CK Brierley1,4, R Revuelta Iniesta2, N Storrar3, A Thomas4 1 Department of Haematology, Oxford University Hospitals NHS Trust, UK; 2Department of Child Life and Health, University of Edinburgh, Edinburgh, UK; 3Department of Haematology, Western General Hospital, Crewe Road, Edinburgh, UK; 4Department of Paediatric Haematology, Royal Hospital for Sick Children, Edinburgh, UK Iron overload contributes to long-term adverse outcomes following ALL survival. In a cohort of children with ALL we assessed ferritin levels, bone marrow aspirate (BMA) iron stores, transfusion burden and incidence of iron overload over the course of treatment. Extreme hyperferritinaemia (ferritin >10,000 lg/l) is thought to be pathogonomic for haemophagocytic lymphohistiocytosis (HLH), a complication of ALL. Incidence of HLH was assessed. 28 patients presenting to the Royal Hospital for Sick Children, Edinburgh with a new diagnosis of ALL between August 2010 and January 2014 were included. Median age at diagnosis was 3.5 years (4 weeks – 15 years). Median haemoglobin at diagnosis was 79 g/l (range 32–109). Patients received a median of 195 ml/kg (range 45– 570) packed red blood cells, corresponding to a median iron burden of 130 mg/kg (range 30–380). High-risk disease was predictive of increased red cell requirements (standard-risk 150 ml/kg versus highrisk 281 ml/kg, p = 0.01). At diagnosis the median ferritin was 629 lg/l (76–2790) and at 3 months 1403 lg/l (224–6882). Ferritin was significantly higher in the high-risk cohort than the standard-risk (median 2089 lg/l versus 698 lg/l, p = 0.006). End-of-treatment ferritin values normalised in only 1 patient, with a median of 864 lg/l (69–3822). Overall, 26/28 (93%) had a ferritin >500 lg/l during the course of treatment and 3/ 28(11%) demonstrated extreme hyperferritinaemia (>10,000 lg/l), without evidence of HLH. Median BMA iron grade at day 28 was 2.5(0–4) and 3.5(2–5) at end of treatment. There was no significant correlation between serum ferritin and BMA iron store assessed at either 28 days or at end of treatment. 6/9 (67%) BMAs at end of treatment demonstrated heavy iron staining consistent with iron overload. Serum ferritin is an unreliable measure of iron burden, and BMA iron staining essential in the assessment of iron status in ALL. Children with high-risk disease have the highest transfusion rates, exposing this population to significant risk of iron overload and related toxicity.

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

24 Quantitative PCR using patient specific primers detects occult central nervous system involvement in more than one-third of children with acute lymphoblastic leukaemia YM Yousafzai1, S Bhatti1, AVE Smith2, LM Smith2, A Cousins1, W Taylor3, A Spence3, FM Fee2, MT Gardiner2, J Kolle2, B Gibson3, N Heaney3, S Chudleigh3, C Halsey1,3 1 Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK; 2Molecular Diagnostics (MRD group), New South Glasgow Labs, Southern General Hospital, Glasgow, UK; 3Department of Paediatric Haematology, Royal Hospital for Sick Children, Glasgow, UK Despite the excellent overall survival in childhood acute lymphoblastic leukaemia (ALL), central nervous system (CNS) disease continues to pose challenges. Currently, only 3–5% children with ALL present with cytological evidence of CNS involvement, however the majority of CNS relapses occur in children who had negative CNS cytospins at diagnosis. There is a clear need for improving diagnostic accuracy of CNS disease. Leukaemic cells, being clonal in origin, carry VDJ gene rearrangements unique to individual patients. TaqMan qPCR identification of leukaemia using allele specific oligonucleotides (or ASO primers) targeting these rearrangements provides accurate assessment of submicroscopic levels of leukaemia in the bone marrow. We investigated whether this method can be utilized to identify patients with submicroscopic levels of CNS disease. After obtaining informed consent from 57 patients with ALL, diagnostic cerebrospinal fluid (CSF) samples were collected. Following careful investigation of the most suitable methods for DNA extraction and quantification, CSF samples were tested for presence of leukaemic DNA. Samples from 38 patients with no evidence of CNS disease were suitable for analysis. Samples from 15/38 patients (39.5%) tested positive by qPCR. In 7 qPCR positive patients, two sets of ASO primers/patient were tested. Notably, qPCR amplification was seen in only 1/2 primer sets in 3/7 patients suggesting possible clonal diversity between CNS and BM populations. CSF qPCR positivity was seen in patients with both high- and low-risk clinical and cytogenetic features. Follow up samples from 19 patients collected at the end of induction were also tested. All samples tested negative by qPCR suggesting clearance of CNS disease. Overall, these findings suggest that sub-clinical CNS disease is likely to be present in more than one third of newly diagnosed patients. This study highlights the lack of sensitivity in diagnosing CNS disease with cytological methods and provides a rationale for risk-stratified CNS-directed therapy.


Free Communication: Paediatrics

25 Central venous line placement prior to induction therapy in children with acute lymphoblastic leukaemia does not increase the risk of line-related thrombosis S Dhir1, P Connor2, E Chalmers3, M Cummins4, A Qureshi5, K Iqbal1, Z Howard2, A Ajanaku2, L Amu3, P Avery6, S Samarasinghe7, T Biss8 1 Department of Paediatric and Adolescent Haematology and Oncology, Newcastle Hospitals NHS Trust, UK; 2 Department of Paediatric Haematology and Oncology, Noah’s Arc Children’s Hospital for Wales, Cardiff, UK; 3 Department of Paediatric Haematology, Royal Hospital for Sick Children, Glasgow, UK; 4Department of Paediatric Haematology, Bristol Royal Hospital for Children, Bristol, UK; 5Department of Paediatric Haematology, Children’s Hospital, Oxford University Hospital Trust, Oxford, UK; 6 School of Mathematics and Statistics, Newcastle University, Newcastle upon Tyne, UK; 7Department of Haematology and Oncology, Great Ormond Street Hospital, London, UK; 8 Department of Haematology, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, UK Thrombosis is a treatment-related complication of acute lymphoblastic leukaemia (ALL) in children, occurring at its highest frequency during induction therapy following exposure to asparaginase and steroid. There is variation in practice between UK centres in the timing of central venous line (CVL) placement in children with ALL. Whilst some perform ‘early’ placement, prior to induction, others ‘delay’ until end of induction due to concern that the risk of CVL-related thrombosis may be greater with early line placement. This study aimed to determine whether the rate of CVL-related thrombosis differs between centres which perform ‘early’ versus ‘delayed’ CVL placement. Data were collected retrospectively over a 10-year period, 2004– 2013, from centres using identical treatment regimens. CVL-related thrombosis was defined as symptomatic, radiologically-confirmed thrombus in neck/limb vein contiguous to CVL site. No centre used thromboprophylaxis or routine surveillance for CVL-related thrombosis. Nine CVL-related thrombotic events occurred in 972 CVLs in 5 centres (0.9%). In the ‘early’ group thrombosis occurred in 5/ 618 (0.8%), while the rate was 4/354 (1.1%) in the ‘delayed’ group (p = 0.62, Chi-square test). Median time from CVL placement to thrombosis was 24 days (range: 1–157). 4/5 events in CVLs placed ‘early’ occurred during induction, the other on day 37 of therapy. Children with thrombosis had a median age of 13 years (range: 6-17). CVL type was upper venous system Hickman in 5 and portacath in 3, common femoral vein line in 1. All received therapeutic anticoagulation with low molecular weight heparin for a median of 4 months. Complications were pulmonary embolism (n = 1),


thrombus extension to involve cerebral veins (n = 1), mild postthrombotic syndrome (n = 1), delay in chemotherapy (n = 5). Incidence of CVL-related thrombosis is low and not influenced by timing of CVL placement. Early CVL placement may be preferred in order to reduce the physical/psychological distress of peripheral venous access in children undergoing therapy for ALL.

26 The presence of non-tumour T and B lymphocytes in diagnostic bone marrow is associated with improved overall survival in childhood common acute lymphoblastic leukaemia C Edwin1, J Dean2, R Keenan2, P McNamara1,2, K Phillips1 1 Institute of Child Health, University of Liverpool, UK; 2 Alder Hey Children’s Hospital NHS Foundation Trust, Liverpool, UK With survival rates in paediatric acute lymphoblastic leukaemia (ALL) increasing over recent decades and the limits of chemotherapy being reached, recent immunological research in acute leukaemia has focused on the absolute lymphocyte count (ALC) in peripheral blood at day-29 as a means to refine risk stratification for treatment, and improve prognostication. If these lymphocytes in the blood are indicating an anti-leukaemia response it would be expected to find these lymphocytes in the bone marrow where most of the leukaemia cells are located. In this study, 55 retrospective sets of diagnostic flow cytometry data from bone marrow in children with common ALL were analysed to look at the presence of normal non-tumour lymphocytes and relate these to overall (OS) and event-free survival (EFS). The presence of higher numbers of normal CD20 expressing B cells was associated with a significant improvement in OS (median in survivors=3.11 (IQR 1.62–5.35) (%) (n = 47) and non-survivors = 1.55 (IQR 0.585–2.20) (%) (n = 8) (p = 0.045). The presence of normal CD7 expressing T cells showed a strong but non-significant trend with survival; median in survivors 6.32 (IQR 3.40–9.89) (%) compared to non-survivors and 4.18 (IQR 2.24–5.47) (%) in non-survivors (p = 0.070). Subsequent Kaplan–Meier survival analysis on transformed data showed that CD20 expression in the nontumour population above and below an expression threshold of 2.57% showed a mean survival time of 118.3 months (SE 10.07) (CI 98.57–138.03) with CD20 expression ≤2.57% compared to 142.6 months (SE 5.22) (CI 132.44–152.91) in those >2.57% this gave a significant difference (p = 0.031); further analysis of CD7 illustrated a similar trend towards significance. We demonstrate that the presence of normal B and T cells in bone marrow at diagnosis of common acute lymphoblastic leukaemia correlates with improved survival. This data suggests that there is an anti-tumour immune response warranting further investigation.

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Free Communication: Presidential Session

Free Communication Presidential Session 27 SPIRIT 2: an NCRI randomised study comparing dasatinib with imatinib in patients with newly diagnosed chronic myeloid leukaemia – 2 year follow up

28 Haemoglobinopathy survey - a picture of transfusion for sickle cell disease and thalassaemia in 11 London hospitals

WL Osborne1, SG O’Brien1, C Hedgley1, L Foroni2, J Apperley2, P Terril1, P Rowe1, J McCullough1, T Holyoake3, C Pocock4, J Byrne5, R Bescoby1, M Copland3, R Clark6 1 Northern Institute for Cancer Research, Newcastle University Medical School, UK; 2Centre for Haematology, Imperial College, London, UK; 3Paul O’Gorman Research Centre, University of Glasgow, UK; 4Kent and Canterbury Hospital, UK 5Faculty of Medicine and Health Sciences, Nottingham University, UK; 6Department of Molecular and Cancer Medicine, University of Liverpool, UK

S Trompeter1,2, A Mora3, E Wong4, D Collett4, P Bolton-Maggs5, D Poles5, A Deary3, A Watt5, L Williamson6 1 Department of Haematology, University College London Hospitals NHS Foundation Trust, UK; 2Patient Services, NHS Blood and Transplant, Colindale, London, UK; 3NHS Blood and Transplant, Clinical Trials Unit, Cambridge, UK; 4NHS Blood and Transplant, Statistics and Clinical Studies, Bristol, UK; 5Serious Hazards of Transfusion (SHOT), SHOT Office, Manchester Blood Centre, UK; 6NHS Blood and Transplant, Watford, UK

SPIRIT 2 is the largest trial comparing imatinib 400 mg with dasatinib 100 mg daily. 814 newly diagnosed patients were recruited from 144 hospitals in the UK between August 2008 and March 2013. 812 patients were randomised, 406 in each arm. The primary end point of the study is event-free survival at 5 years. A key secondary endpoint is rate of a major molecular response (MMR, MR3, BCRABL1/ABL ratio 10 9 109/l (27 AIDA, 30 chemo-free). Outcomes: With follow-up to 1/1/14 (median 30.5 m), 90% entered morphological CR; day-30,-60 mortality is 5%, 7%. Excluding deaths 60 years (n = 49) 77%). There was no significant difference in CR (Chemo 89%, Chemofree 94%; p = 0.18). Day-30,-60 mortalities were 6% versus 4% (p = 0.6), 9% versus 5% (p = 0.2). Twelve chemo patients have haematologically relapsed (+7 molecular relapses) versus 1 chemofree patient (CIR 13% versus 1%, HR 0.16 (0.05–0.48), p = 0.001). Cumulative incidence of molecular relapse is 27% versus 0%, 4-year OS 89% versus 95%, HR 0.60 (0.26–1.42), p = 0.2. There was significantly less alopecia, liver, GI toxicity among chemofree patients, and fewer blood/platelet transfusions, days on antibiotics. There was no heterogeneity of treatment by subgroup. Low-risk patients (WBC10 9 109/l) CIR was 26% versus 0% (p = 0.008), OS 87% versus 84% (p = 0.8): 28/30 high-risk chemo-free patients received GO (OS 89%). Conclusion: ATO+ATRA represents a new standard-of-care, with very low risk of relapse and excellent survival. The approach is safe and effective in high-risk patients particularly if combined with a single dose of GO. Our attenuated ATO schedule yields minimal toxicity, without reduced efficacy. ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Free Communication: Presidential Session

31 Discovery of novel genes underlying inherited bleeding and platelet disorders by genome sequencing TK Bariana, on behalf of the BRIDGE Bleeding and Platelet Disorder Consortium Katherine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London, UK The BRIDGE-BPD consortium is a multi-centre collaboration working to phenotype and genome sequence patients with inherited bleeding and platelet disorders (BPD) of unknown molecular aetiology with the aim to identify novel genes. Patients with unexplained BPDs are eligible for enrolment if there is a high likelihood of the condition being inherited and laboratory investigations have excluded cases caused by mutations in known BPD genes. Clinical phenotype and laboratory data of 958 cases have been recorded on a database using an agreed case report form. We have used Human Phenotype Ontology (HPO) terms to comprehensively capture the clinical heterogeneity and developed a novel algorithm to cluster cases based on phenotypic similarity. We show that 60% of index cases were annotated with HPO terms indicating abnormalities in organ systems other than blood or blood forming tissues, particularly the nervous and skeletal systems. Using a common genome sequencing and variant calling approach and a joint statistical analysis for all cases we have discovered novel genes causative of BPD at 5q13, 5q31, 18q11 and 20q11. In addition we replicated recent discoveries by others that GFI1B (9q34), RASGRP2 (11q13) and ACTN1 (14q24) are novel BPD genes. The clinical and laboratory phenotypes observed in the patients which were at the basis of the discovery of the novel genes will be reviewed. In conclusion the use of large-scale genome sequence analysis of patients with unexplained BPDs has so far led to the discovery of four novel genes and confirmed the observations of three further genes already identified by others. Such discoveries improve our understanding of the molecular basis of this class of disorders and the newly discovered genes have been included on the ThromboGenomics next generation sequencing platform for the comprehensive and affordable diagnosis of inherited BPDs.

32 Childhood pre-B acute lymphoblastic leukaemia cells capable of central nervous system engraftment are common, heterogeneous and transit the blood-cerebrospinal fluid barrier YM Yousafzai1, MTS Williams1, S Bhatti1, A Cousins1, K Rehe2, S Bomken2, P Sinclair2, VJ Weston3, LJ Russell2, O Heidenreich2, JAE Irving2, J Vormoor2, GJ Graham1, C Halsey1,4 1 Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK; 2Northern Institute for Cancer Research, Newcastle University, UK; 3School of Cancer Sciences, University of Birmingham, UK; 4Department of Paediatric Haematology, Royal Hospital for Sick Children, Glasgow, UK Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Despite this, mechanisms of CNS infiltration are poorly understood and the timing, frequency and properties of BCP-ALL blasts entering the CNS compartment are unknown. Using primary ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

blasts from children with newly diagnosed BCP-ALL we investigated CNS-engrafting potential and whether CNS entry is determined by chemokine receptors. Xenotransplantation into immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice resulted in CNS engraftment in 23/29 diagnostic samples (79%), 2/2 from patients with overt CNS disease and 21/27 (70%) from patients thought to be CNS-negative at initial lumbar puncture. CNS engraftment was seen in samples with both high and low risk clinical features. Histological findings resemble human pathology and demonstrate that leukaemic cells transit the blood-cerebrospinal-fluid (CSF) barrier. CNS leukaemia initiating cells appeared to be frequent as CNS engraftment was seen in 5/6 mice following intrafemoral transplantation of as few as 10 leukaemic cells. In addition flow-sorting of the diagnostic samples into different maturation stages (CD10high/low, CD20high/low or CD34high/low) did not show any hierarchical structure in CNS engrafting potential. Leukaemic cells retrieved from the murine CNS expressed the chemokine receptors CXCR3 and CXCR4, whilst CSF samples from children with evidence of CNS infiltration showed lower levels of the CXCR3 ligands CXCL9 and CXCL10, and the CXCR4 ligand CXCL12. This suggests local consumption of ligands may be occurring. However, comparison between bone marrow and CNS populations indicates chemokine receptors do not actively direct leukaemic cell migration to the CNS. Overall, these findings suggest that sub-clinical seeding of the CNS in ALL is likely to be present in the majority of patients at the time of original diagnosis and efforts to prevent CNS relapse should concentrate on augmenting effective eradication of disease from this site rather than targeting entry mechanisms.

33 Leukaemia-associated somatic mutations drive distinct patterns of age-related clonal haemopoiesis T McKerrell1, N Park2, T Moreno3, C Grove1, H Ponstingl1, J Stephens4,5, Understanding Society Scientific Group6, C Crawley7, J Craig7, M Scott7, C Hodkinson8, J Baxter8, R Rad9,10, DR Forsyth11, MA Quail2, E Zeggini12, W Ouwehand4,5, I Varela3, GS Vassiliou1,4, T McKerrell and N Park contributed equally to the research project 1 Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK; 2Sequencing Research Group, Wellcome Trust Sanger Institute, Cambridge, UK; 3Instituto de Biomedicina y Biotecnologıa de Cantabria (CSIC-UCSodercan), Departamento de Biologıa Molecular, Universidad de Cantabria, Santander, Spain; 4Department of Haematology, University of Cambridge, Cambridge, UK; 5 NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK; 6Institute for Social and Economic Research, University of Essex, Colchester, UK; 7Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge, UK; 8Cambridge Blood and Stem Cell Biobank, Department of Haematology, University of Cambridge, Cambridge, UK; 9Department of Medicine II, Klinikum €t Mu € nchen, Mu € nchen, Rechts der Isar, Technische Universita Germany; 10German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; 11 Department of Medicine for the Elderly, Cambridge University Hospitals NHS Trust, Cambridge, UK; 12Human Genetics, Wellcome Trust Sanger Institute, Cambridge, UK Clonal haemopoiesis driven by leukaemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this


Free Communication: Presidential Session phenomenon, we interrogated 15 mutation hotspots in blood DNA from 4219 individuals using ultra-deep sequencing. Using only the hotspots studied, we identified clonal haemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years; predicting that clonal haemopoiesis is much more prevalent overall than was previously realized. Indeed, using our findings as a basis for projection, we estimate the overall prevalence of age related clonal haemopoiesis (ARCH) to be >70% in those older than 90 years. DNMT3A-R882 mutations were most common and, although their incidence


increased with age, were found in individuals as young as 25 years. By contrast mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were only identified in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures operating in the ageing haemopoietic system and explains the rising incidence of myelodysplastic syndromes with advancing age.

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Free Communication: Lymphoid Malignancies

Wednesday 22nd April 2015 Free Communication Lymphoid Malignancies 34 Second interim analysis of a phase 3 study of idelalisib plus rituximab (R) for relapsed chronic lymphocytic leukaemia (CLL): efficacy analysis in patient subpopulations with Del(17p) and other adverse prognostic factors T Munir1, P Hillmen1, J Sharman2, S Coutre3, R Furman4, B Cheson5, J Pagel6, J Barrientos7, A Zelenetz8, T Kipps9, I Flinn10, P Ghia11, M Hallek12, B Coiffier13, S O’Brien14, E Tausch15, K Kreuzer12, W Jiang16, M Lazarov16, D Li16, T Jahn16, S Stilgenbauer15 1 Department of Haematology, St James’ University Hospital, Leeds, UK; 2Willamette Valley Cancer Institute, US Oncology Research, Springfield, OR, USA; 3Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; 4 Weill Cornell Medical College, New York Presbyterian Hospital, New York, USA; 5Georgetown University Hospital, Washington, DC, USA; 6Fred Hutchinson Cancer Research Center, Seattle, USA; 7North Shore-LIJ School of Medicine, New Hyde Park, NY, USA; 8Memorial Sloan-Kettering Cancer Center, New York, USA; 9Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; 10Sarah Cannon  Vita-Salute Cancer Institute, Nashville, TN, USA; 11Universita San Raffaele, Milan, Italy; 12University of Cologne, Cologne, Germany; 13Hospices Civils de Lyon, University of Lyon, Pierre-Benite, France; 14University of Texas MD Anderson Cancer Center, Houston, TX, USA; 15University of Ulm, Ulm, Germany; 16Gilead Sciences, Foster City, CA, USA Idelalisib, an oral inhibitor of PI3Kd, was recently approved for the treatment of relapsed CLL in combination with rituximab (IDELA+R). This report describes results from the second interim analysis of the Phase 3 study evaluating IDELA+R. The study evaluated IDELA+R versus placebo (PBO)+R in patients with CLL requiring therapy after progression 38°C with neutrophil count 95% of the total expenditure. The aim was to evaluate reasons for the increase in HMD tests and whether testing was in line with local guidance from 2006. We conducted a retrospective audit of send-away HMD tests over a 3-month period, their clinical indications and appropriateness of testing against local guidance. Sixty-three patients evaluated had 102 tests requested on peripheral and/or bone marrow. Forty-three of 49 (87%) immunophenotyping tests, and all 7 (100%) BCR-ABL tests were appropriate. Only 17 of 36 (47%) cytogenetics tests fulfilled the local guidance. Ten JAK-2 samples (not included on the 2006 guidelines) were requested, of which 3 (30%) were in patients who did not fulfil the BCSH criteria for polycythaemia and thrombocytosis investigations. Overall 28% of HMD tests were inappropriate, representing a projected £41,500 per annum cost. Trainees highlighted that they took extra samples ‘just in case’ and these were often sent away even if not indicated. Updated local guidelines were drafted, in line with local consultants, based on clinical utility and taking national guidance into account. It was also recommended that consultants support trainees by documenting which bone marrow tests are required. Following these implementations, a re-audit was undertaken. 98 tests were recorded in 77 patients, compared to 102 for 63 in the previous audit. Overall, 88% of tests were in line with the new guideline. Consultants did not express any concerns that patient care was affected by fewer tests being performed. This audit highlights that local guidance and support of junior staff on the judicious use of expensive HMD tests can better utilise NHS resources without compromising patient care.

58 Idiopathic systemic capillary leak syndrome treated successfully with maintenance intravenous immunoglobulin AJ King1, K Ramasamy1, C Lahoz2 1 Department of Haematology, Churchill Hospital, Oxford, UK; 2Department of Haematology, Wexham Park Hospital, Slough, UK Idiopathic systemic capillary leak syndrome (ISCLS) is a rare systemic disease characterized by recurrent episodes of haemoconcentration, hypoalbuminaemia and hypotension. An associated paraprotein is usually detected. Diagnosis is difficult; patients are often referred to haematology because of the erythrocytosis. A 60-year-old gentleman was referred to haematology clinic because of a haemoglobin of 200 g/l. This was discovered after presentation with an ischaemic right leg requiring embolectomy. Previous blood counts were normal, and his haemoglobin normalized post-operatively. Marked oedema was noted post-operatively which resolved. Testing for the JAK2V617F mutation was negative, his serum erythropoietin was normal (8.4 IU/l (NR 5–20)) and an abdominal ultrasound was unremarkable. A bone marrow biopsy showed normal appearances; testing for the JAK2 exon 12 mutation was negative. A month later, he felt non-specifically unwell and then presented with acute kidney injury, a haemoglobin of 221 g/l and oedema. The diagnosis of ISCLS was considered at this point. Serum electrophoresis showed a small IgG paraprotein and he met the clinical criteria for ISCLS. He was therefore started on terbutaline and aminophylline. Unfortunately, he continued to experience severe episodes, culminating in an admission with an erythrocytosis (haemoglobin was 226 g/l), bilateral limb ischaemia and bilateral lower limb compartment syndrome requiring embolectomies and fasciotomies ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

respectively. Intensive care treatment was necessary post-operatively. Because maintenance intravenous immunoglobin (IvIg) has been shown to be effective at reducing attacks, an application was made to the IvIg panel. After approval, a dose of 1 g/kg was begun monthly. Six months later, he has had no further attacks and remains well. ISCLS is a life-threatening condition and is almost certainly under-recognised: this is the third case one of the authors has encountered in the last 4 years. Prompt recognition is important to ensure appropriate treatment is given. Treatment with maintenance intravenous immunoglobulin appears markedly effective at reducing the frequency of attacks.

59 Management of the ‘Choose and Book’ system for polycythaemia/thrombocytosis by the MPN specialist nurse L Wallis, J Chacko, S Killick Department of Haematology, Royal Bournemouth Hospital, UK Choose and Book is a national service that combines electronic booking and a choice of place, date and time for first hospital or clinic appointments. The aim is to provide choice for patients and may prevent DNAs as patients are able to choose the time and date of their first appointment. At the Royal Bournemouth Hospital, appointments are made available within the general haematology clinics and traditionally the patient may be seen by a Haematologist or a Specialist Registrar for their first appointment. Prior to ‘Choose and Book’, referrals for this type of patient were over a hundred a year. Following the implementation of this system there are referrals which relate to ‘advice and guidance’. These are time consuming for the Consultant Haematologist. This DGH has an experienced MPN specialist nurse, currently running 2 clinics a week for both MPN patients and those with secondary polycythaemia. Two double appointment slots were created for new patients per week. Over 60 referrals were passed onto the specialist nurse over the last 6 months of 2014. These have been audited to show:

• Who made the referral • Type of referral (‘Choose and Book’ or ‘Advice and Guidance’) • What action was taken on receipt of the referral • The reason for the referral The result of this change in practice has been the availability of the Consultant for other work. The diagnostic tests can be streamlined by the specialist nurse and essential tests carried out before the patient is first seen. The patient is seen by a professional specialising in these conditions and is given continuity, with subsequent appointments being carried out by the same individual. There may be opportunity in the future to provide further education for GPs relating to the timing of referrals to haematology for polycythaemia. This may be a system that can be adopted by other hospitals.


Poster Session: General Haematology

60 A single centre review of the use and outcomes of cranial imaging for in-patients with haematological malignancies AJ Doyle, R Carr Department of Haematology, Guy’s & St Thomas’ NHS Foundation Trust, London, UK Patients with haematological malignancies presenting with neurological symptoms and signs provide several clinical concerns including disease spread, intracranial haemorrhage secondary to thrombocytopenia and infections particularly of opportunistic organisms whilst immunosuppressed. In particular, magnetic resonance imaging (MRI) is preferable for investigating lymphomatous CNS-spread over computer tomography (CT). We reviewed 452 haematological malignancy admissions (diagnoses including lymphoma, myeloma and leukaemia) over a 12-month period. 37 cranial scans were performed on 27 patients in response to new symptoms (35) or to assess disease response (2); 20 were CT and 17 were MRI. Indications were: focal neurological signs 15 (41%), acute confusion 6(16%), reduced consciousness 4(11%), headache 4(11%), seizures 2(7%) and traumatic head injuries 2(7%). 35% (7/20) of CT scans and 82% (14/17) of MRI scans provided diagnostic information leading to a change in management for 11 patients; these included CNS-targeted chemotherapy, palliation, high-dose dexamethasone, antimicrobial therapy and additional transfusion support. This review showed that CT was frequently used as a ‘screening’ tool to evaluate unexplained neurological symptoms and was less likely to yield useful information, whereas MRI was used more often in those with focal neurological signs and had a higher diagnostic yield. Likewise, five negative CT scans were the consequence of requests on patients for whom MRI was the more appropriate modality and two patients received both CT and MRI when MRI would have been more appropriate from the onset of symptoms retrospectively. For both of these cases, MRI provided additional diagnostic information to CT. Clinicians should have a specific diagnostic concern to determine the appropriate imaging modality given the patients’ underlying disease. Furthermore, the low yield from CT should be considered in the light of the radiation exposure and resource availability.

61 The development and review of performance assessment scoring in blood films for parasites external quality assessment DM Pelling, B De la Salle, K Hyde UK NEQAS for General Haematology, UK In response to the requirement for EQA to reflect current practices, UK NEQAS for General Haematology has implemented a change to the way in which performance is assessed for participants who subscribe to the Blood Films for Parasite Identification EQA scheme. This change will see the implementation of a two-stage scoring process that takes into account the participant’s service repertoire, participant expertise, and provides feedback to participants which reflects clinical significance. Stage 1 scoring focuses on parasite screening only, will be applicable to all participants and will require participants to record whether the case distributed is positive or negative, and if positive, identify only the parasite type: malaria, filaria, trypanosome, other, rather than provide a full species identification; full species identification for malaria parasites will be a required and assessed element of stage 2 scoring, for those laboratories providing


that service, when it is implemented. Real-time shadow scoring on the first three distributed surveys (six separate cases) in 2014 has been completed. Data from 495 laboratories were reviewed with 487 (98.4%) laboratories being included in the shadow scoring, thereby giving a total of 2799 individually scored results. The 487 laboratories comprised 309 (63.4%) UK and 178 (36.6%) non-UK laboratories. 436 (89.5%) of participants made no errors over the review period of which 294 (67.4%) were UK-based. Of the 2799 results scored, 63 (2.25%) were incorrect, with slightly more than half (50.8%) of these being false negative responses. 18 of the 32 false negative results (56.3%) were seen when microfilaria slides were distributed; recent UK NEQAS (H) reports have addressed this trend and emphasised the need to examine slides at low power to ensure microfilaria infections are not missed. Overall, laboratories are providing accurate parasite screening and thereby allowing timely and effective treatment to be initiated.

62 Second line treatment for immune thrombocytopenia (ITP): a review of patients with immune thrombocytopenia in Basildon Hospital KLM White, PD Jasani Haematology, Basildon Hospital, UK ITP is an autoimmune disorder characterized by immunologic destruction of otherwise normal platelets, most commonly occurring in response to an unknown stimulus. Currently there are evidence-based guidelines for primary treatment of this condition but there is a dearth of good quality evidence to guide second and subsequent lines of management. Commonly used agents in the UK for second line treatment are Rituximab and the newer thrombopoietin receptor agonists (TPO) – Romiplostim and Eltrombopag. Therefore, we decided to review the second line management and their success in our ITP patients. Notes were obtained for all patients with primary ITP who had received second line treatment since July 2008. Information was collected for each patient on the second line agents used; the platelet count pre and post treatment (the highest recorded) and the duration of response (classified according to the International Working Group guidelines (IWG)). Patients in whom there was a good response who also had overlapping primary treatment were discounted. A mean duration (in weeks) of response was calculated. In total, there were 11 patients who had multiple second line treatments. Rituximab had an average response duration of 50 weeks, Romiplostim of 19 weeks and Eltrombopag of 19 weeks. With Rituximab the response tended to be complete or not at all, whereas everyone responded for a minimum of 4 weeks with the TPOs. A long-term response was maintained in 36% of patients with Rituximab, 27% with Romiplostim, 18% with Eltrombopag and 18% of patients had no response to either agent. In conclusion, patients generally responded to one agent and Rituximab had the longest duration of response. However, more data needs to be collected on a bigger sample size of patients and more patients should be given the TPO agonists as first relapse treatment to enable fair comparison between the agents.

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Poster Session: General Haematology

63 Carbapenem resistant gram negative organisms as emerging pathogens in neutropenic fever M Grech, A Giotas, A Gatt, DJ Camilleri Department of Haematology-Oncology, Mater Dei Hospital, Msida, Malta Neutropenic fever and sepsis are considered to be among the primary causes of morbidity and mortality in patients with haematological malignancy being treated with intensive chemotherapy. Identification of the causative organisms and their susceptibility patterns is therefore imperative to provide effective initial antibiotic cover. The aims of this study were to identify the causative agents of neutropenic fever episodes in our patients and to investigate the local pattern of antibiotic susceptibilities. A retrospective review of haematology patients treated for neutropenic fever in Mater Dei Hospital during the period of April 2013 to March 2014 was carried out. Patients aged 18 years or older, with febrile neutropenia secondary to chemotherapy or underlying disease were included. A systematic review of case notes and culture and sensitivity reports was performed. A total of 112 patients (61 males, 51 females) with 275 episodes of febrile neutropenia were identified. The most common diagnoses were high grade non-Hodgkin lymphoma (NHL) (32.2%), acute leukaemia (25.9%) and low grade NHL (13.4%). 47% of patients had positive cultures. In 77% of all culture positive episodes, a Gram negative organism was cultured. The most common Gram negative organisms were E. coli (34.2%), Klebsiella spp (24.6%) and P. aeruginosa (5.3%). The most common Gram positive organisms were coagulase negative Staphylococci (11.8%) and Enterococci (7.5%). Approximately 30% of Gram negative organisms were resistant to piperacillin/tazobactam and around 20% were resistant to gentamicin. 10.4% of Gram negative bacteria were resistant to meropenem. All of the Gram positive isolates were susceptible to vancomycin. 10.5% of all Gram negative isolates were carbapenem resistant Enterobacteriaceae, all of which were Klebsiella pneumoniae. Of these, 92.3% were sensitive to colistin and all were sensitive to tigecycline. This study shows that in our department, Gram negative organisms remain the commonest pathogens isolated in patients with neutropenic fever and that there is a considerable incidence of multidrug resistant organisms.

64 Integration of haemato-oncology and palliative care services and staff perceptions to referral AK White, C Hockings, C McNamara Department of Haematology, The Royal Free Hospital, London, UK Integration of palliative care services (PCS) with haemato-oncology (HO) patients is a quality standard in Britain. Healthcare professionals face difficult management decisions in defining the point at which further chemotherapy is appropriate and when a change to a more palliative approach should be pursued. The aim of this study was to characterise referrals to PCS in patients with HO malignancies and barriers to early and appropriate referral. We reviewed notes for adult inpatients dying of HO disease in a large teaching hospital between 2009–14. Information regarding PCS referral and discussions around dying was collected. An anonymous survey was sent to staff regarding PCS input. There were 49 patient deaths available for analysis. Of 33 patients who received curative therapy, 30% were referred to PCS. Of 11 ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

patients receiving treatment without curative intent, 73% had PCS referral. 4 of 5 patients receiving no therapy were referred. 15 of the 49 deaths occurred in ICU, none of which had PCS input. Documentation of discussions around death occurred in 34 cases (69%). Preferred place of death was discussed in 17 of these (35% of total). Review of multi-disciplinary meeting (MDM) records showed that in only 2 cases discussion around PCS referral occurred. The majority of patients had a documented discussion about death. Referral rates to PCS were generally high, however none of the ICU patients had PCS input, despite frequent documented recognition of deterioration. This highlights a possible role for PCS in HO patients in the ICU setting. Documentation of PCS input in MDM meetings was poor, possibly due to subsequent progression of disease, or death being unexpected. The survey of healthcare professionals confirmed the value of PCS input and that referral is often made too late. Early integration with PCS and HO is a quality standard and the MDM setting provides an opportunity for this.

65 A survey of genetic haemochromatosis testing pattern in a tertiary centre M Lamoudi1, S Keeney2, C West1, K Ryan1, J Thachil1, R Krishna1 1 Department of Haematology, Manchester Royal Infirmary, UK; 2Molecular Diagnostics Centre, Central Manchester University Hospitals NHS Foundation Trust, UK Genetic testing for hereditary haemochromatosis type 1 (HH) is used to confirm the diagnosis of suspected HH or as a predictive test. More than 90% of patients with clinically characterized HH are homozygous for the HFE C282Y variant. However, the penetrance of disease in C282Y homozygotes is incomplete. Therefore, in suspected cases, referral for HFE genotyping should be based on the presence of both elevated serum ferritin and transferrin saturation (tsat), in line with extant guidelines. To identify prior serum ferritin and tsat phenotypic testing and their values in order to assess appropriateness of patient referrals for HFE genotyping through our direct GP and hospital Trust referral pathway over a 3 year period (2012–2014). The number of patients tested for HFE mutations was ascertained (n = 998). We documented their genotypes, whether they had both ferritin and tsat levels tested, and whether these levels were raised. Of the 998 patients tested, 91 patients were homozygous for C282Y, 223 heterozygous for C282Y, 65 compound heterozygous for C282Y/H63D, and 19 homozygous for H63D. Prior test results for 873/ 998 were available. 95.4% (n = 833) had their serum ferritin measured. Of those, 67.8% (n = 564) had a raised ferritin. 75.4% (n = 658) had tsat measured, of those, 31.8% (209) had a raised level. Only 31.7% (n = 277) had both ferritin and tsat levels checked prior to referral for genetic testing. Whilst the above figures do not identify cases referred on a predictive basis (follow up family studies) they do indicate that baseline checking of ferritin and transferrin saturation prior to genotyping remains low, at variance with HH clinical and genetic diagnostic guidelines. Appropriate phenotypic testing and clinical evaluation algorithms should be put in place to ensure that genetic laboratories are not burdened with unnecessary tests, reducing financial and manpower costs.


Poster Session: General Haematology

66 Autologous 111In- labelled platelet scan as a predictor of splenectomy outcome in ITP S Kazi1, F Mckiddie2, R Kerr3, M Drummond4, H Roddie5, C Stirling6, J Anderson7, M McColl8, N Priddie7, HG Watson1 1 Department of Haematology, Aberdeen Royal Infirmary, Foresterhill Health Campus, UK; 2Department of Nuclear Medicine, Aberdeen Royal Infirmary, UK; 3Department of Haematology, Ninewells Hospital, Dundee, UK; 4Department of Haematology, Western Infirmary, Glasgow, UK; 5 Department of Haematology, Western general Hospital, Edinburgh, UK; 6Department of Haematology, RAH, Paisley, UK; 7Department of Haematology, Royal Infirmary Edinburgh, UK; 8Department of Haematology, University Hospital Crosshouse, Kilmarnock, Ayrshire, UK The second line management of ITP is heterogeneous with variable use of splenectomy, licensed thrombopoietin receptor agonists and unlicensed immunosuppressants. It has been suggested that decisions to perform splenectomy can be guided by patterns of platelet uptake. We did a retrospective study of 30 primary ITP patients who underwent 111In- labelled platelet sequestration studies between 2009 and 2014. Scintigraphic images were obtained 30 minutes, 4, 24, 48, 72 and 96 hours post administration of labelled platelets. Ratios were then calculated for liver and spleen. Data were gathered on the patient outcomes following the sequestration studies. In patients who underwent splenectomy, we reviewed platelet counts at 1 month, 3 months and at a recent consultation. Majority of patients showed splenic pattern of sequestration (SS) (16/30). Four patients had hepatic sequestration (HS) and 8 a mixed platelet sequestration (MS) (liver and spleen). One patient had a normal platelet sequestration study and in one the study was inconclusive. Of the 16 patients with splenic pattern of sequestration, six have undergone and one is awaiting splenectomy, two refused splenectomy, two were lost to follow up, two have not required second line treatment thus far, one is on a trial of TPO-receptor agonist and data are missing in two. Overall 10/30 patients have undergone splenectomy. Of these ten, six patients had SS, two had MS, one had HS and one had a normal study. All patients who have undergone splenectomy remain in complete remission as observed from their current platelet counts (mean 26.5 months [range 3–67 months]). At present our data do not demonstrate a difference in outcome of splenectomy dependent on site of platelet sequestration but this may reflect low numbers.

67 An email advice service for non-urgent general practitioners’ haematological queries A Aggarwal, AJ King, D Hay Department of Haematology, Churchill Hospital, Oxford, UK General practitioners frequently require advice from haematologists regarding blood test results. The most appropriate pathway for nonurgent queries is often unclear: options include phoning the haematologist on call, writing to the department or simply referring the patient to clinic. To address this we established a secure email service for Oxfordshire GPs using an address. It is checked daily by the on-call haematology speciality registrar with the aim of responding within 48 hours. All responses sent by a registrar are reviewed and authorised electronically by a consultant within 24 hours. Over a 3-month period, 180 email queries were received. The most common queries regarded neutropenia (26; 14.4%), followed by erythrocytosis (15; 8.3%), anaemia (13; 7.2%), immunoglobulin


results (13; 7.2%) and thrombocytosis (12; 6.7%). Of the 180 queries, 20 (11.1%) were reviewed in clinic for further investigation. A survey was conducted of GP users. Of 64 responses, 97% of GPs were satisfied overall with the service, and 86% were satisfied with the speed of reply. Without the email advice service, 13% would have referred their patient to clinic. 66% would have called the haematologist on call and 22% would have written a letter for advice. This model of providing non-urgent advice offers significant advantages. It provides a clear point of contact for non-urgent queries, an audit trail of the advice given, and an excellent training opportunity for registrars. It allows queries to be answered rapidly yet at a time convenient to the registrar, with ample opportunity to review the patients’ blood results and other relevant information. Finally, it is a theoretical source of income generation for the haematology department, and is clearly of utility in reducing unnecessary referrals to secondary care. We recommend all departments consider developing a similar service.

68 Hickman line infection rates, causative organisms and impacts on recurrence - a retrospective analysis at the James Cook University Hospital, Middlesbrough T Creasey Department of Haematology, James Cook University Hospital, Middlesbrough, UK Hickman lines are a valuable means of intravascular access for haematology patients, particularly those receiving intensive chemotherapy. However, they are also a significant source of infection in immunosuppressed patients. The purpose of this study was firstly to investigate the frequency of Hickman line related infections, including causative organisms. Subsequently, the management of these infections was audited and compared with reference guidelines from the Infectious Diseases Society of America. Where line salvage was attempted, recurrence rates based on individual organisms was then evaluated. Retrospective data was collected on 60 consecutively inserted Hickman lines over a period of 8 months between 24/10/13 and 16/ 06/14. All growth detected from Hickman line cultures and peripheral blood cultures was recorded. Based on approved guidelines for the diagnosis of catheter-related blood stream infections (CRBSI), all episodes of bacterial growth were placed into one of 4 categories: Confirmed CRBSI, Suspected CRBSI, Hickman line colonisation and Other source of bacteraemia. Results indicated that 13% of the Hickman lines in the study had a confirmed CRBSI, 10% had a suspected CRBSI, 22% had an episode of bacterial colonisation. In 3%, a bacteraemia was attributable to a non-line related source and in 52% no positive growth was detected or blood culture sampling had not been required over the study period. The treatment of confirmed CRBSI, suspected CRBSI and line colonisation was then assessed based on line removal or salvage. 15 affected Hickman lines were removed and 12 salvaged. Of the salvaged lines, eight developed a recurrent CRBSI, although only 3 of these were with the same organism. All 11 infections with organisms that require line removal according to consensus guidelines were managed appropriately. A trend was noted with increased recurrence rates when infections with gram negative organisms were managed with attempted line salvage.

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Poster Session: General Haematology

69 Management of anaemia in a resource limited setting: an observational study of current practice at Queen Elizabeth Central Hospital, Malawi N Redding1, R Perry-Thomas2 1 Department of Haematology, James Cook University Hospital, Middlesbrough, UK; 2School of Medicine, University of St Andrews, UK Anaemia is common in Africa and is associated with significant morbidity and mortality. Existing data, based on studies with HIV-negative subjects, suggests empirical treatment with iron replacement, anthelmintics and anti-malarials. However, the aetiology of reversible anaemia in HIV-positive individuals differs from that in HIV-negative patients. An observational study was conducted on 102 adult medical inpatients in Queen Elizabeth Central Hospital, Malawi to review anaemia management in this area of high HIV prevalence. Haemoglobin levels ranged from 19 to 167 g/l; 70% of the cohort were anaemic and 36% had severe anaemia (Hb250) accessible on a web based e-learning platform (PathXL) to simulate common diagnostic challenges faced in laboratory haematology. We developed interactive tutorials to teach basic skills: understanding the full blood count; interpretation of a blood film; instructional videos; clinical case scenarios and mock examinations. The VLE was evaluated using formal/informal feedback in several learning environments. Self- directed learning: 40 clinical trainees and 10 biomedical scientists reviewed the VLE and all of them found it ‘useful’ or ‘very useful’ and would recommend it to colleagues. Junior trainees valued


Poster Session: General Haematology the instructional videos, clinical scenarios on emergencies and annotated practice cases. Large group teaching: Cases for a regional teaching day were hosted online with access to all participants before and during the event. 53/88 (60%) trainees had reviewed the cases, 78% (69/88) attendees rated the training experience as very good (5/5). Feedback included ‘really enjoyed digital microscopy; the most useful day this year.’ Small group teaching: All 7 (100%) trainees, participating in a 45minute peer-led training session found the VLE a useful tool for morphology training and enjoyed the interaction within the group. The VLE is an innovative means of bridging the training gaps created by operational/regulatory changes in laboratory haematology by providing 24/7 access to multiple users for self-directed learning and delivering formal teaching in small/large groups.

72 New conclusions in scintigraphy: results of sickle cell disease bone involvements HA Al-Jafar1, SM AlDallal1, J Al-Shemmeri2, H AlHaran3, NS Al-Ali4, RA Hashem5, S Al-Enizi3, U Afzal6, L Aytoglu7, E Al-Shemmeri6 1 Department of Haematology, Amiri Hospital, Kuwait City, Kuwait; 2Department of Nuclear Medicine, Kuwait University, Kuwait City, Kuwait; 3Al-Razi Hospital, Kuwait City, Kuwait; 4Department of Endocrinology, Amiri Hospital, Kuwait City, Kuwait; 5Amiri Hospital, Kuwait City, Kuwait; 6 Department of Nuclear Medicine, Al-Farwania Hospital, Kuwait City, Kuwait; 7Department of Nuclear Medicine, Jabir Al-Ahmad Center, Kuwait City, Kuwait Sickle cells disease (SCD) is an inherited haemoglobinopathy characterized by abnormally shaped red blood cells. The abnormal haemoglobin tends to polymerise under low oxygen concentration or increased body oxygen demands. Therefore, red blood cells become less pliable and are abnormally sticking. Some red blood cells become distorted into the sickle shape leading to tissue infraction and progressive organ damage (Beutler, Lichtman, Coller, Kipps, & Seligsohn, 2001). Many sophisticated imaging techniques are in used now a days starting from radiographs, bone scans (BS), Magnetic resonance Imaging (MRI), and Single Photon Emission Computed Tomography (SPECT). This study in its preliminary phase revealed an important findings: 1- Spontaneous bone regeneration in sickle cell disease avascular necrosis (AVN) is a landmark observation in this project by using scintigraphy, which could encourage more research work on using bone-rebuilding medications to restore the bone integrity. 2- SPECT/CT is safe and quick procedure. It gives the necessary information to localize AVN lesion in SCD patients. It gives better recognize of the lesion from anatomical and functional point of view (Nikpoor, 2009). It is more accurate than BS alone or MRI alone, because CT is more accurate to detect bone lesion than MRI, where MRI more accurate for soft tissue diagnosis. 3- Spontaneous bone regeneration in AVN in some SCD patients in our study is encouraging to find out why it is happened and what medical measures could be applied to protect the patients bones before it become advanced and irreversible lesions . For that task of encourage AVN healing we sated up another project to treat AVN in SCD medically.


73 A regional review of maternal thrombocytopenia AM Dillon, B Myers Department of Haematology, Lincoln County Hospital, UK Maternal thrombocytopenia is common, with a prevalence of 6–11% ( 0.05). The mean age was 45 years (range 16–82 years) and 33.3% (n = 18) were aged> 60 years. A significant difference in overall survival was detected between patients >60 years of age and those 60 years died. Seven of these (87.5%) deaths occurred in the early stages of therapy. There was a positive correlation between age and ECOG performance status (Spearman r 0.49; p = 0.0002) and a negative correlation between age and eGFR (Pearson r = 0.5; p = 0.0001) and albumin levels (Pearson r = 0.5; p = 0.0001) but not with stage, BMI, height, weight or LDH. We concluded that the younger the patients are at diagnosis, the better the overall survival (OS). However there is no correlation between BMI and OS for our population.

134 Outcomes from a single centre for patients with multiply relapsed myeloma treated with bendamustine containing regimens NG Ryman, S Hannigan, MW Jenner Department of Haematology, Southampton General Hospital, UK Bendamustine is a bifunctional alkylating agent. It has shown activity in myeloma in both the upfront and relapse settings, including patients with renal insufficiency. In the literature bendamustine has been used with steroids in combination with lenalidamide, bortezomib or thalidomide. The main toxicity is myelosuppression. Over a 3 year period, eleven patients with multiply relapsed myeloma received a bendamustine containing regimen. The median age was 67 years (range 58–78). Bendamustine was combined with steroids in all cases. It was combined in eight patients with thalidomide, in two patients with lenalidomide and in one patient with bortezomib. Combination therapy was selected based on the efficacy and toxicity of prior therapy. The dose of bendamustine used was 60–100 mg/m2 for two days per 28 day cycles. The patients had had a median of four previous lines of therapy. Nine of the eleven had received prior thalidomide, bortezomib and lenalidomide. Eight had had an autologous stem cell transplant. Five had poor risk cytogenetics (defined by the presence of one or more of t (4;14), t (14;16), del (1p), gain (1q) or del (17p)) including one ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Poster Session: Lymphoid Malignancy – Clinical patient with 17p deletion. Patients received a median of four cycles of chemotherapy (range 2–6). Using IMWG response criteria, three of eleven patients (27%) achieved a partial response including one with poor risk cytogenetics. Four (36%) had stable disease. Four had progressive disease on treatment. Eight of the eleven went on to have at least one further line of treatment (range 0–5). The progression free survival was six months with an overall survival of 14 months (range 3–41 months). Conclusion: This was a heavily pre-treated group of myeloma patients where bendamustine was the only new agent used. In keeping with other studies, our data supports the potential role for bendamustine combinations as a useful strategy in multiply relapsed myeloma.

135 Estimation of the clinical benefit of idelalisib in double-refractory follicular lymphoma: Inference from uncontrolled study results P Fox1, W Sullivan2, D Lee2, JG Castaigne3, J Cole3, A Hatswell2 1 Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, UK; 2BresMed Health Solution, Sheffield, UK; 3Gilead Sciences, London, UK Idelalisib was licensed in September 2014 by the European Medicines Agency for use in follicular lymphoma (FL) patients refractory to two prior treatments based on results of a single-arm phase 2 study of 72 FL patients (study 101–09). To estimate the relative clinical benefit of idelalisib for such patients - with limited conventional treatment options -, we have extrapolated individual patient data from 101–09 using three analytic frameworks. The first comparison considered time to progression results for idelalisib as reported in 101–09, versus results from the previous line of therapy (typically combination immunochemotherapy, for which we conservatively assumed that equivalent disease control could be achieved with re-treatment). Post-progression survival was assumed to be identical. Using this framework, idelalisib-treated patients were estimated to survive a mean of 0.61 years longer than retreatment with the previous regimen (3.65 versus 3.04 life years). This reflected the higher response rate (and response durability) as compared to the previous line of therapy. The second approach was to compare idelalisib with no active treatment, reflecting FL patients too frail to receive further cytotoxicbased interventions. It was assumed that patients who did not receive treatment would experience the same outcomes as non-responders in the study 101–09. Using this framework the model predicted that patients treated with idelalisib survived 0.49 years longer (3.50 versus 3.01 life years). The third approach provides an ‘edge case’ assumption that untreated patients would progress immediately, and experience only the post-progression survival seen in study 101–09. This approach estimated that idelalisib provides 0.80 additional life years (3.65 versus 2.45 life years). Although there remains some uncertainty due to the non-randomised nature of study 101–09, the novel approaches presented give plausible estimates of the additional survival afforded by idelalisib for FL patients refractory to two prior treatments.

136 Update on a phase 2 study of idelalisib in combination with rituximab in treatment-na€ıve patients ≥65 years with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) R Dubowy1, S O’Brien2, N Lamanna3, T Kipps4, I Flinn5, A Zelenetz6, J Burger2, L Holes1, Y Cho1, S Coutre7 1 Gilead Sciences, Foster City, USA; 2University of Texas, MD Anderson Cancer Center, USA; 3Columbia University Medical Center, New York, USA; 4Moores Cancer Center, University of California, San Diego, La Jolla, USA; 5Sarah Cancer Institute Nashville, TN, USA; 6Memorial Sloan-Kettering Cancer Center, New York, USA; 7Stanford Cancer Institute, Stanford University School of Medicine, CA, USA Idelalisib (IDELA) in combination with rituximab (R), has been previously reported to yield a 97% ORR in treatment na€ıve patients ≥65 years with CLL or SLL (O’Brien, ASCO 2013). This report is an update on that initial cohort of study patients. 64 patients were enrolled (59 CLL/5 SLL) with median age of 71 years and 14% with del (17p)/TP53 mutation. 43 patients completed the 48 week primary study and 41 entered the extension study. 21 patients discontinued from the primary study and 17 from the extension study leaving 24 patients on-going. The median IDELA exposure is 22.9 months with 13 (20%) patients treated for more than 36 months. The ORRis 97% (78% PR, 19% CR) with 3% non-evaluable; median time to response is 1.9 months. The median PFS is not reached, 95% CI (37.3 months,–). Of note, 9/9 patients with del (17p)/TP53 mutation responded (3 CR, 6 PR); 5 discontinued for AE (4) or investigator request (1) and 4 remain on treatment. The most frequent Gr ≥3 AEs (%) were diarrhoea/colitis (42), pneumonia (19), rash (13), dehydration (8), UTI (6), dyspnoea (5) and respiratory failure (5). Pneumonitis developed in 2 patents, both Gr 5, and one patient with diverticulitis developed bowel perforation. The median time to onset of Gr ≥3 diarrhoea/colitis was 9.5 months, (range 3–29). Re-challenge was attempted in 21 of the 27 patients with Gr ≥3 diarrhoea/colitis, and 12 patients were able to resume IDELA for ≥ 120 days. 15 (23%) patients developed Gr ≥3 ALT or AST elevation, all recovering, with successful resumption of IDELA, at a reduced dose, in 12. In total, 29 (45%) patients had one or more treatment-emergent AEs leading to IDELA dose reduction. In conclusion, the responses are durable, including in those with del (17p)/TP53 mutation, with diarrhoea/colitis the most common Gr ≥3 AE.

137 Outcome of transplantation in mantle cell lymphoma at University Hospitals Leicester – a single centre experience HS Walter1, S Ladani1, F Miall1, AM Martin1, K Hodgson1, MJS Dyer1, B Kennedy1, SD Wagner1, A Bowen2, M Lyttleton3, R Lewin1, A Hunter1 1 Department of Haematology, University Hospitals Leicester, UK; 2Department of Haematology, Northampton General Hospital, UK; 3Department of Haematology, Kettering General Hospital, UK Despite recent advances in clinical practice, mantle cell lymphoma (MCL) is associated with a reduced overall survival in comparison with low grade B cell non-Hodgkin’s lymphoma. The role of hematopoietic progenitor cell transplant (HPCT) in MCL remains unclear.

ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104


Poster Session: Lymphoid Malignancy – Clinical We have assessed the outcome in those patients who have received an allogeneic HPCT (Allo-HPCT) for MCL at University Hospitals Leicester (UHL), where an early transplant intervention approach has been adopted. From December 2003 to August 2014, 20 patients with MCL were allografted; 4 female and 16 males of median age 58.5 years (range 37–68). 2 patients had received prior autografts. Indications for AlloHPCT were young age, entry into a national trial, partial response (PR) and relapsed disease. Pre-transplant chemotherapy consisted of RCHOP and RCHOP/high dose Ara C in 13 patients. The remainder received either FCR or an RCHOP based regimen (RCHOP/FMD, RCHOP/IVE and RCHOP/methotrexate). 2 received intrathecal chemotherapy. Of the 17 patients transplanted after 1 line of chemotherapy, 14 were in complete response (CR) and 3 in PR. Following 2 lines, 2 were in PR and 1 in CR. No patient received more than 2 lines of chemotherapy. 13 patients received conditioning with fludarabine, melfalan and alemtuzumab and 7 received alentuzumab LEAM/BEAM. 8 Allo-HPCT were sibling and 12 MUD (9/10 or 10/ 10 matches). All received cyclosporin A for GvHD prophylaxis. Median length of follow up is 34.3 months. 13 patients are alive; 11 remain in CR, 2 have relapsed and are currently receiving a BTK inhibitor with radiological CR. 7 have died, 5 with relapsed disease (2 intrathecal) and 2 of TRM (days +128 and +908, 1 prior AutoHPCT). Of those receiving 2 lines of prior chemotherapy, 2 have died and 1 has relapsed. Median PFS is 35.1 months (range 3.9– 127). These results support the early use of Allo-HPCT in MCL.

138 Follow up in de novo diffuse large B cell lymphoma patients treated with RCHOP: a new approach SH Burrows, M Ewings, SL Allford Department of Haematology, Musgrove Park Hospital, Taunton, UK Follow up strategy for patients treated for high grade lymphoma varies according to local practice. The emphasis of appointments is usually detection of relapse. Internationally cross-sectional imaging has been used, although no improvement in outcomes has been shown. In the UK usual practice is to undertake clinical review for 5 years following treatment. However after reviewing our survival data we have changed our practice at Musgrove Park Hospital. All patients treated with R-CHOP for de novo DLBCL were identified (earliest case November 2003). In total 259 patients achieved complete or partial remission by radiological criteria. Analysis of disease free survival curves showed that relapse beyond two years after treatment was rare, but did still occur beyond 5 years. The cohort still in remission at two years (n = 145) was therefore identified for further analysis. Only seven patients subsequently relapsed, giving disease free survival for this group of 90% as of December 2014 (Kaplan-Meier method). We reviewed the notes to determine whether routine follow up appointments played any role in detection of these late relapses. Five patients self-referred with symptoms between appointments. Two patients waited for routine appointments to report recurrent symptoms. In all cases patients had themselves noticed symptoms of relapse, and in two cases actually delayed presentation until their planned review. We concluded that routine clinical assessment beyond two years does not improve the care of patients with de novo DLBCL who achieve remission with R-CHOP chemotherapy. We have instead introduced an annual ‘Lymphoma Wellbeing Clinic’ for these patients. This takes the form of a seminar lead by a specialist nurse and a haematology consultant who give presentations on returning to normal


life after treatment, late effects, symptoms of relapse and appropriate contact routes for any patients with concerns. This has been well received by patients, and reduced unnecessary clinic attendances.

139 Audit of central nervous system (CNS) prophylaxis in patient with diffuse large B-cell lymphoma (DLBCL) AB Qadri, M Wells, D Yallop, P Patten, S Devereux, R Marcus, S Kassam Department of Haematology, King’s College Hospital, London, UK The outcome of secondary CNS relapse in DLBCL is dismal. However, identifying those at high-risk and the method of CNS prophylaxis is controversial. Centres use high dose intravenous methotrexate (HDMXT), intrathecal methotrexate (IT-MXT) or both. BSCH guidelines have been published recommending IT-MXT alone, and therefore we conducted a retrospective audit of our practice. Sixty-one patients were diagnosed with de-novo DLBCL between 2008 and 2013. Fifty-five (90%) were treated with curative intent. Seventeen patients (31%), 9 male, median age 56 (range 33–74) were identified as high-risk for CNS relapse defined as >1 extranodal site with raised LDH, anatomical proximity to the CNS, HIV infection or testicular involvement. Nine (53%) patients were scheduled to receive IT -MXT alone, 7 (41%) both HD-MXT and IT-MXT and 1 (6%) HD-MXT only. For the 16 patients receiving IT-MXT, median number of doses was 3.5 (range 1–6). One patient did not complete all planned doses due to persistent headache. Of the 8 patients scheduled for 3 courses of HD-MXT, 3 (38%) patients did not complete all courses due to patient frailty (1), mucositis and volume overload (1) and patient refusal (1). Two of 55 (4%) patients ultimately relapsed in the CNS. One had HIV infection, stage 1E disease (bone) and had received 3 doses of IT-MXT. The other had not fulfilled criteria for high-risk, hence had not received prophylaxis. If criteria suggested by the BSCH for identifying high-risk patients had been followed, 11 (20%) patients would have been treated. Neither of our patients who ultimately relapsed in the CNS would have been included. In conclusion, the risk of CNS relapse in DLBCL is low, however identifying the population at risk remains challenging. Better risk stratification is required to enable appropriately directed therapy with minimal toxicity.

140 Single centre experience of a Bruton’s tyrosine kinase (BTK) specific inhibitor (ONO-4059) in relapsed mantle cell lymphoma (MCL) HS Walter1, CV Hutchinson1, J Sharpe2, K Duffy2, A Nishimura2, S Abe2, H Honda3, T Yasuhiro3, T Yoshizawa3, J Birkett2, N Courtenay-Luck2, MJS Dyer1 1 Department of Haematology, University Hospitals Leicester, UK; 2ONO Pharma UK LTD, London, UK; 3Ono Pharmaceutical Co. Ltd., Osaka, Japan MCL follows an aggressive clinical course. Despite the use of chemoimmunotherapy and haematopoietic progenitor cell transplantation most patients will relapse and die from their disease. The BTK inhibitor ibrutinib has shown considerable efficacy in relapsed MCL (response rate 68% and median progression-free survival (PFS) 13.9 months), but second generation, more specific inhibitors are now entering the clinic. We report our experience of the BTK-specific inhibitor ONO 4059 in relapsed/refractory MCL. Five patients, ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Poster Session: Lymphoid Malignancy – Clinical with biopsy-proven relapsed mantle cell lymphoma of median age 67 years (range 54–78) were recruited at Leicester Royal Infirmary from September 2013 onto a Phase I clinical trial (NCT01659255). All had received at least two prior systemic therapies (range 2–4) and 2 patients had undergone allogeneic stem cell transplantation; no patients had blastoid MCL. These 5 patients were recruited to dose levels 320 mg – 600 mg OD. Two patients experienced skin toxicity at the 600 mg level during cycle 1, of which one was dose limiting; biopsy showed non-specific drug induced rash with infiltration of Cyclin D1 negative polyclonal B-cells. Both cases resolved rapidly on interruption of therapy and did not recur on reintroduction at 480 mg OD. One patient had a grade 3 leukocytosis on treatment initiation, which resolved during the first four weeks of therapy. ONO-4059 was well tolerated, with no diarrhoea, nausea, arthralgia or bleeding as reported with first generation BTK inhibitors. Response to treatment assessed by computerised tomography showed 4 good partial responses and 1 complete response in one patient who had been allografted. All patients remain well and continue on ONO-4059. The median time on treatment is 9 months (range 2–16). These and other preliminary data indicate that ONO4059 has significant clinical activity and is well tolerated in MCL and other B-cell malignancies, even in patients who have previously undergone allogeneic stem cell transplantation.

141 Single-agent ibrutinib for the treatment of mantle cell lymphoma (MCL): evaluating the link between durable response and quality of life (QoL) in the SPARK study S Rule1, A Goy2, P Martin3, R Ramchandren4, J Alexeeva5, R Popat6, I Avivi7, R Advani8, S Le Gouill9, N Horowitz10, Z Yuan11, B Kranenburg12, SH Zhuang11, W Deraedt13, A Rizo11, W Wildgust11, M Wang14 1 Derriford Hospital, Plymouth, UK; 2John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA; 3Weill Cornell Medical College, New York, NY, USA; 4Wayne State University Hudson-Webber Cancer Research Center, Karmanos Cancer Center, Detroit, MI, USA; 5Federal Medical Research Center, V.A. Almazov, StPetersburg, Russia; 6NIHR/Wellcome Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, UK; 7Tel Aviv Medical Center, Tel Aviv, Israel; 8Stanford Cancer Institute, Stanford, CA, USA; 9 matologie clinique CHU de Nantes (France), Service d’he quipe 10, Nantes, France; 10Rambam INSERM UMR 892 e Health Care Campus, Haifa, Israel; 11Janssen Research & Development, LLC, Raritan, NJ, USA; 12Janssen Biologics B.V., The Netherlands; 13Janssen Research & Development, LLC, Beerse, Belgium; 14The University of Texas MD Anderson Cancer Center, Houston, TX, USA Despite recent advances, MCL remains difficult to treat with frequent chemoresistance in the relapsed/refractory setting. Ibrutinib, a first-inclass, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, has demonstrated durable single-agent efficacy in patients with previously-treated MCL in a prior phase 2 study (Wang, et al. [2013] NEJM, 369,507). The phase 2 SPARK study further evaluated the efficacy and safety of single-agent ibrutinib specifically in patients with MCL who had received a rituximab-containing regimen and had progressed after ≥2 cycles of bortezomib therapy. In this multicentre, single-arm study, patients were enrolled to receive continuous treatment with 560 mg/ day ibrutinib orally once-daily until progressive disease (PD) or unacceptable toxicity. Primary end point was the overall response rate in ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

response evaluable patients, as assessed by an Independent Review Committee. Secondary end points included patient-reported outcomes (FACT-Lym). Overall, 25/110 evaluable patients (22.7%) were considered to have primary resistant disease (PD at first disease evaluation), with 85/110 (77.3%) considered as ‘responders’: 22 (20%) were considered to have moderate response (stable disease [SD] or better, but with PD within 12 months; MR group), and 63 (57.3%) were considered to have durable response (SD or better, maintained for >12 months; DR group). Median progression-free survival for the total evaluable population was 10.5 months; 4.1 months for the MR group and 16.8 months for the DR group. Additionally, 67/109 evaluable patients (61.5%) achieved a clinically-meaningful improvement in lymphoma symptoms (based on a change of ≥5 points on the FACTLym), with 57 of the 80 ‘responders’ who had a post-baseline FACTLym evaluation (71.3%) achieving this clinically-meaningful level of improved QoL. In conclusion, single agent ibrutinib was highly efficacious in this study with a majority of patients responding to therapy and achieving long, durable remissions. Moreover, patients with clinical responses to ibrutinib also tended to show clinically-meaningful improvements in QoL.

142 Life-threatening bowel perforation while on thalidomide-based triplet regimen for multiple myeloma: a retrospective case series P Sriskandarajah, FR Scott, S Muthalali, JE Mercieca Department of Haematology, Epsom and St Helier Hospital, Surrey, UK Thalidomide is an oral agent which has demonstrated significant anti-myeloma activity resulting in improved progression-free and overall survival rates in newly diagnosed multiple myeloma patients. The mechanisms of action of Thalidomide are complex, including both antiangiogenic and immunomodulatory properties. However, as well as targeting neoplastic plasma cells, Thalidomide can affect other organ systems resulting in toxicities. One potential adverse effect includes gastrointestinal disturbance, particularly diverticulitis and perforation. This has previously been recorded as an uncommon adverse reaction, with 95% OS. Both ABVD and escalated BEACOPP showed lower relapse rates than expected from trial data. The lack of relapses and relative sparing of IFRT in high risk escalated BEACOPP patients provides justification for using this more intensive strategy for young poorer prognosis patients.

147 Incidence of complex karyotype in CLL patients at King’s College Hospital tertiary referral practice: implications for novel therapies CE Graham, H Gilbert, B Czepulkowski, R Ireland, S Kassam, D Yallop, R Marcus, S Devereux, P Patten Department of Haematology, King’s College Hospital, London, UK In CLL, FISH alone has largely replaced analysis by conventional cytogenetics due to better yield and knowledge of well described prognostic groups in patients treated with chemo-immunotherapy. However, all FISH prognostic groups respond well to BCR inhibitor therapies such as ibrutinib. Recently, Thompson et al (ASH 2014) reported patients with associated complex karyotype (CK, ≥3 structural changes) respond less well (and therefore may need additional intervention such as allogeneic BMT) with good responses in noncomplex (non-CK) cases. We therefore reviewed our incidence of CK correlating with FISH prognostic group (good risk=13q-/normal, intermediate risk= tri12, poor risk = p53- & ATM-). Of 212 CLL patients (from 2006–2014), 108 had 1 or more cytogenetic and/or FISH samples processed, resulting in 261 cytogenetic ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

requests. Overall, 72% of cytogenetic samples processed produced a result, with CK identified in 49 samples. 26% of patients tested had CK at some point during their disease course. Overall, 12%, 14% & 54% in the good, intermediate and poor risk FISH groups respectively had CK. Conversely, 67% of CK cases and 20% of non-CK cases had poor risk FISH. Specifically examining 17p abnormalities by cytogenetics, 8 patients had derivative or deleted chromosome 17. p53- was confirmed by FISH in 6 of these samples (7 tested). A total of 23 samples (from 16 patients) demonstrated p53- by FISH of which 87% had CK. Overall, we find CK occurs in one quarter of patients from this complex tertiary referral practice and this is not limited to those individuals with poor risk FISH. Furthermore, 46% of patients with perceived poor prognosis due to FISH (p53- ATM-) might be expected to have long durable responses with novel therapies as these cases lack CK. Therefore, continued full evaluation of patients with both FISH and cytogenetics is likely to be indicated in the future.

148 Off trial use of brentuximab vedotin in Hodgkin lymphoma – a regional experience

JA Browning1, CS Hatton1, S Mucklow2, R Sampson2, H Grech2, GP Collins1 1 Department of Haematology, Churchill Hospital, Oxford, UK; 2Department of Haematology, Royal Berkshire Hospital, Reading, UK The efficacy of brentuximab vedotin (BV) in Hodgkin lymphoma (HL) was established in a phase II study (Younes et al [2012] J Clin Oncol, 30, 2183). Patients with relapsed / refractory HL, post autograft, were treated with up to 16 cycles of BV with response assessment. Here, we report data from a retrospective study of all patients treated off trial with BV for relapsed HL in one of two UK centres with all treatment plans reviewed by the same specialist, regional multi-disciplinary team. The aim was to compare outcomes from this group of unselected patients to published phase II data. Treatment was according to accepted protocols (1.8 mg/kg, 3 weekly cycle) with up to 16 cycles. All patients were assessed by PET-CT prior to treatment with BV. PET-CT assessment of response was typically after the 3rd cycle. Loss of response was confirmed by PETCT. 16 patients with relapsed HL (10 male, 6 female; median age 52, range 18 to 73) were included. Each patient had received a median of 3.5 separate chemotherapy treatments before BV (range 1 to 7). 8 patients had received a prior autograft. A median of 5.0 BV cycles were given (range 1 to 16). 69% of patients responded to BV (CR or PR). 6% showed stable disease. Median duration of response was 167 days (range 40 to 877). Median progression free survival was 206 days (range 11 to 1009). Post BV treatment 5 patients (31%) proceeded to allograft and 3 (19%) to autograft. Compared with the pivotal phase II study, this patient group was older, the number of cycles of BV per patient was lower yet response rates were similar. This confirms that in an unselected patient population BV causes marked responses in relapsed HL and is useful treatment, particularly in bridging to autograft / allograft.


Poster Session: Lymphoid Malignancy – Clinical

149 How does myeloma present in the 21st century? H Bielby, F Luizzi, K Ryan, J Thachil, E Tholouli, R Krishna Department of Haematology, Manchester Royal Infirmary, UK The management of multiple myeloma has been revolutionised in the current era with the advent of novel agents. Earlier diagnosis of this condition is preferable to aid in earlier treatment and thus improved prognosis in these patients. The aim of the study was to determine the clinical and laboratory prolife of patients presenting with myeloma in a tertiary centre. Electronic records of all myeloma patients attending the specialist myeloma clinic in two calendar months were included. Data collected included age, sex, staging and the parameters of the CRAB diagnostic criteria namely Hypercalcemia, Renal impairment, Anaemia and Bony lytic lesions. Of 145 patients, 86 (59%) were male and 59 (41%) female. 12 (8%)patients were below age of 50 years and 51 (35%)patients were above the age of 70 years. 37 (25%) had light chain myeloma and 13 (8%)patients had both elevated para protein and light chains. At diagnosis, 76 (64%) patients had bony lesions, 84 (71%) had anaemia, 59 (50%) had renal impairment and 13 (11%) had hypercalcemia. The combinations of diagnostic CRAB criteria have been summarised with anaemia/ bony lesion (AB)being most common combination (18%)followed by RAB (16%) and RA (15%) and no patient having just isolated hypercalcemia. Bony lesions were most common in the spine (38) followed by pelvis and skull (both 20). Most patients (71%) were in ISS stage 2 (35%) and 3 (36%). Patients are usually in advanced stages (2 or 3) according to the ISS stage at the time of diagnosis. Anaemia and bony lytic lesions are usually the disease defining criteria followed by renal impairment. These patients may be presenting to either their general practitioner or non-haematologist and the diagnosis may be overlooked causing delay in diagnosis. It is important to disseminate epidemiological information for earlier diagnosis in this era of novel agents.

150 Single centre experience of R-mini CHOP for the treatment of elderly patients with diffuse large B-cell lymphoma P Dighe, S Garcia, M Ceesay, S Bowcock, C DeLord, B Vadher, R Marcus, S Devereux, P Patten, D Yallop, S Kassam Department of Haematology, Kings College Hospital, London, UK Diffuse large B-cell lymphoma (DLBCL) is a common cancer in the elderly but is challenging to treat. Favourable outcomes have been reported using R-mini-CHOP. We retrospectively reviewed outcomes for patients treated with this regimen in our centre. Twenty-two patients, 15 female, median age 83 years (range 76–93) were treated between 2010 and 2014. Twenty-one had de novo DLBCL, and 1 had transformation from low-grade lymphoma. Fourteen (64%) patients had stage III/IV disease, 11 (50%) had a performance score >2 and 19 (86%) had a high-risk IPI score. Twenty patients had an ejection fraction >50%, in 2 patients this was not documented. Charlson scores projected an average life-expectancy of 63% at 1 year. The median number of chemotherapy cycles received was 6 (range 1–8). All patients received pre-emptive GCSF. FDG-PET scanning was used to assess response in 14/22 (64%) patients. Twelve (55%) patients responded (10 complete and 2 partial responses),


with a median response duration of 12 months (range 3–18). Only 2 responding patients have relapsed. At a median follow up of 7 months (range 1–44) the median overall survival is 10 months. Ten (45%) patients have died; 8 of progressive lymphoma, 1 treatment-related sepsis and 1 stroke. Documented grade 3/4 haematological toxicity occurred in 3/22 (14%) patients. All these patients experienced episodes of febrile neutropenia. Nine (41%) patients developed grade 3/4 non-haematological toxicity; non-neutropenic infections (6), steroid-induced anxiety (1), atrial fibrillation/ischaemic stroke (1), myopathy/peripheral neuropathy (1). Three (14%) patients required dose reductions and 7 (32%) patients tolerated dose escalation following the first cycle of chemotherapy. These results confirm that it is possible to treat elderly/frail patients with high-risk DLBCL with an anthracycline-containing regimen. Meaningful responses with manageable toxicity are achievable and dose escalation can be considered.

151 Safety and efficacy of bendamustine use in patients with chronic lymphocytic leukaemia JHP Lam, T Corbett Department of Haematology, Royal Sussex County Hospital, Brighton and Sussex University Hospitals NHS Trust, UK Bendamustine is an alkylating agent with unique activity, commonly used as a treatment for chronic lymphocytic leukaemia and lowgrade non-Hodgkin’s lymphoma. The aim of this audit was to evaluate the safety and efficacy of bendamustine in patients with chronic lymphocytic leukemia in Brighton and Sussex University Hospitals NHS Trust. Retrospective case studies of all patients who received bendamustine for chronic lymphocytic leukaemia during the period 2011–2014 were analysed. Responses at 4–6 weeks after termination of chemotherapy were defined and classified into complete response, partial response, stable disease or progressive disease according to International Workshop on Chronic Lymphocytic Leukaemia criteria. A total of 30 patients were identified. Four were excluded because of ongoing treatment or treatment non-compliance. Out of the 26 patients that were included in the study, 17 had prior chemotherapy (relapsed/refractory group). Twenty-two patients also received rituximab and the remaining 4 had bendamustine as a sole agent. Partial response was achieved in 73% (n = 19) of patients. Twenty-three percent (n = 6) of patients had stable disease and 4% (n = 1) developed progressive disease whilst receiving bendamustine. Overall response rates were 100% and 59% in previously untreated and the relapsed/refractory group, respectively. The overall median progression-free survival was 16 months (95% CI 8.4–23.6) using KaplanMeier analysis. Seven patients required the use of granulocyte colony-stimulating factor. Hospitalisation secondary to neutropenic sepsis occurred in 4 cases. Our overall response rates and toxicity levels are in keeping with current literature (Fischer et al [2011] Journal of Clinical Oncology, 29, 26 & Fischer et al [2012] Journal of Clinical Oncology, 30, 26). In summary, treatment with bendamustine is effective and safe in patients with chronic lymphocytic leukaemia.

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Poster Session: Lymphoid Malignancy – Clinical

152 Risk factors associated with the development of infusion-related reactions (IRRs) in patients with chronic lymphocytic leukaemia (CLL) treated with anti-CD20 monoclonal antibodies (mAbs) in combination with chlorambucil: analysis of the prospective, randomised phase III CLL11 study dataset C Freeman1, M Dixon2, R Houghton3, K Humphrey4, G Fingerle-Rowson5, KA Kreuzer6, A Engelke6, M Hallek6, V Goede6 1 Centre of Haemato-Oncology, Barts Cancer Institute, London, UK; 2Department of Biostatistics, Roche Products Limited, Welwyn Garden City, UK; 3Department of Statistical Programming and Analysis, Roche Products Limited, Welwyn Garden City, UK; 4Pharma Development Clinical Science, Roche Products Limited, Welwyn Garden City, UK; 5Pharma Development Clinical Science, F. Hoffmann-La Roche, Basel, Switzerland; 6German CLL Study Group, Department of Internal Medicine, Center of Integrated Oncology CologneBonn, University Hospital Cologne, Cologne, Germany IRRs are a common toxicity observed in patients with B-cell lymphoproliferative disorders treated with anti-CD20 mAbs. In the CLL11 trial (NCT01010061) in previously untreated CLL patients, obinutuzumab (type II, glycoengineered mAb) with chlorambucil achieved faster B-cell depletion and improved response and progression-free survival versus rituximab (type I mAb) with chlorambucil, but increased both the incidence and severity of IRRs. An exploratory analysis of CLL11 data (obinutuzumab, N = 331; rituximab, N = 326) was conducted to understand the risk profile for IRRs in CLL. Potential baseline pre-treatment risk factors were identified a priori. Primary outcome was IRR development with first mAb infusion. Multivariate logistical regression analysis was performed with bootstrapping for internal validation. Risk for any grade IRR with first infusion was increased for obinutuzumab-treated patients (OR 8.4, 95% CI 5.2–13.4) and patients with higher CD20 surface expression (mean fluorescence intensity [MFI] CD20) on CLL cells (OR 3.5, 95% CI 1.9–6.7), greater Fc gamma receptor 3A expression (FccRIIIA, MFI CD16) on peripheral blood NK cells (OR 3.2, 95% CI 1.5–6.8), higher affinity FccRIIIA genotype (VV) (OR 2.3 95% CI 1.1–5.2), more pronounced neutropaenia (OR 0.31, 95% CI 0.15–0.63) and baseline splenomegaly (OR 1.1, 95% CI 1.01–1.15). Higher baseline absolute lymphocyte count (OR 1.8, 95% CI 1.03–3.0), and respiratory comorbidity (OR 1.7, 95% CI 1.07–2.7) also increased risk. For patients receiving obinutuzumab only, MFI was the most important risk determinant CD20 (OR 3.6, 95% CI 1.6–7.9). Treatment received (obinutuzumab>rituximab) confers greatest risk of IRRs in anti-CD20 mAb-treated CLL patients. Tumour burden, target antigen density and FccR expression on NK cells also appear to contribute to risk. Higher IRR rates with obinutuzumab may result from stronger activation upon binding to CD20 on leukaemic cells and enhanced cross-linking between CD20-expressing leukaemic cells and FccRIIIA-bearing effector cells.

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153 Ibrutinib in chronic lymphocytic leukaemia: experience from the East of the network PWJ Russell2, C Gomez1, K Bowles2, G Turner2, S Sadullah1 1 Department of Haematology, James Paget University Hospital, Gorleston, UK; 2Department of Haematology, Norfolk and Norwich University Hospital, Norwich, UK Ibrutinib, a first-in-class Bruton’s Tyrosine Kinase inhibitor, was available to NHS patients with relapsed/refractory Chronic Lymphocytic Leukaemia (CLL) through a Named Patient Supply (NPS) program from April to September 2014, funded by Janssen Pharmaceuticals. Approximately 600 patients with CLL were enrolled in the UK. The James Paget University Hospital treated 23 patients with CLL through the NPS (including 10 patients from the Norfolk and Norwich University Hospital). The patient group was 65.2% male, with a median age of 74 years (range 45–89) and a median of 3 prior lines of therapy (range 1–6). Cytogenetic analysis was available for 20 (87%) patients. Five (25%) patients had 17p deletion, four (20%) had 13q deletion, three (15%) had trisomy 12p, two (10%) had 11q deletion, and six (30%) had no detectable abnormalities. Therapeutic response was assessed in October 2014. Five patients were excluded from the analysis, including four who had received less than eight weeks of treatment and one who had withdrawn from the NPS early. Of the remaining 18 patients, comprising a total of 242 drug-weeks, there was one (5.6%) Clinical Complete Response (CR), four (22.2%) Partial Responses (PR), nine (50%) Partial Responses with Lymphocytosis (PR+L), two (11.1%) with Stable Disease (SD), one (5.6%) with Disease Progression (DP) and histological transformation, and one (5.6%) death from sepsis. The Overall Response Rate (including PR+L patients) was 78%. Notably, both the patient in Clinical CR and the patient with histological transformation had 17p deletion. Common side-effects included diarrhoea (16.7%), upper respiratory tract infections (11.1%), low platelet counts (two-fold increase in 22.2%). None were treatment-limiting. These encouraging early results must be interpreted cautiously, but they suggest that Ibrutinib has similar efficacy and side-effect profiles in the clinic as it does in clinical trials.


Poster Session: Lymphoid Malignancy – Clinical

154 Pattern of cytokine release in patients with chronic lymphocytic leukaemia treated with obinutuzumab and possible relationship with development of infusion related reactions (IRR) C Freeman1, F Morschhauser2, L Sehn3, M Dixon4, R Houghton5, T Lamy6, G Fingerle-Rowson7, E Wassner-Fritsch7, M Hallek8, G Salles9, G Cartron10 1 Centre of Haemato-Oncology, Barts Cancer Institute, London, UK; 2Department of Hematology, Centre gional Universitaire de Lille, Lille, France; Hospitalier Re 3 Centre for Lymphoid Cancer and Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada; 4Department of Biostatistics, Roche Products Limited, Welwyn Garden City, UK; 5Department of Statistical Programming and Analysis, Roche Products Limited, Welwyn Garden City, UK; 6CHU Rennes, Rennes, France; 7Pharma Development Clinical Science, F. Hoffmann-La Roche, Basel, Switzerland; 8German CLL Study Group, Department of Internal Medicine, Center of Integrated Oncology CologneBonn, University Hospital Cologne, Cologne, Germany; 9 Hematologie, Centre Hospitalier Lyon-Sud, Pierre-Benite, France; 10CHU – St Eloi, Montpellier, France Administration of the type I anti-CD20 antibody rituximab has been shown to induce release of pro-inflammatory cytokines in patients with chronic lymphocytic leukaemia (CLL), with greater release noted in patients experiencing infusion-related reactions (IRRs; the occurrence of related signs and symptoms ≤24 hrs after an infusion). The anti-CD20 antibody obinutuzumab, a glycoengineered type II antibody, demonstrates increased direct-cell death, increased antibody-dependent cell-mediated cytotoxicity and reduced complement activation compared with rituximab. Cytokine release following obinutuzumab administration was investigated using a pooled dataset (N = 38) of obinutuzumab-treated relapsed/refractory CLL patients from phase I/II GAUSS (NCT00576758) and GAUGUIN (NCT00517530) trials. Serum samples for cytokine analysis were taken at 4 timepoints for each infusion (pre-/mid-/end of/2–5 hours post-infusion). Cytokines were measured using the Becton-DickinsonTM Cytometric Bead Array, C3/C4 levels with Siemens BNII NephelometerTM and C3a/C5a levels with BD PharmingenTM ELISA kit. Peripheral blood samples for immunophenotyping were also taken before and after each infusion. In total, 35/38 treated patients experienced IRRs during their first obinutuzumab infusion (grade 1/2 = 25, grade 3/4 = 10); symptoms were accompanied by a decrease in circulating B- and natural killer (NK) cells and an increase in pro-inflammatory cytokines (IL6, IL8, TNFa, IFNc). Mid-infusion, patients with baseline absolute lymphocyte count ≥50 9 109/l versus 1 year. Median PFS for this cohort was 3.9 months (95% CI 2.9–5.0) and median OS was 14.6 months (CI 7.4 – 21.8), which mirrors previously published results. On sub-group analysis, there was no statistically significant difference between patients with Lenalidomide as last prior line of therapy versus others. 59% patients discontinued therapy as a result of progressive disease, while only 16% stopped due to toxicity. 69% required dose interruptions with the commonest grade ≥3 toxicities including neutropenia, thrombocytopenia and infection. None of the patients developed peripheral neuropathy. In summary our data confirm that Pomalidomide is an effective and safe therapy in RRMM, with long-term responders benefiting most from the drug. Further research is required to identify predictive biomarkers of response to pomalidomide.

157 Screening for and management of steroidinduced hyperglycaemia (SIH) in haematology outpatients CEL Rogers, J Vidler, E Wellving, D Yallop, A Cox, KF Hunt, S Kassam Haematology, Kings College Hospital NHS Foundation Trust, London, UK High-dose steroids (HDS) are used to treat a range of haematological conditions. In one year we saw five cases of SIH with blood glucose levels >25 mmol/l, two requiring hospital admission. To address this, we piloted a protocol for detection and management of SIH in haematology outpatients, aiming to avoid hyperglycaemia-related hospital admissions without causing hypoglycaemia. Newly diagnosed patients with lymphoma were screened for undiagnosed diabetes using HbA1c (≥6.5%). All patients subsequently prescribed HDS checked capillary blood glucose (CBG) pre-breakfast and pre-evening meal. Pre-meal CBG ≥11.1 mmol/l was considered clinically important SIH. Treatment algorithms were based on initiation and/or dose titration of gliclazide or Humulin I (depending on CBG), aiming for pre-meal CBG 5–11 mmol/l. The protocol was piloted for 12 months and patient feedback was sought via questionnaire. Of 72 patients with newly-diagnosed lymphoma, 19 (26%) had known diabetes, 4 (6%) had screen-detected diabetes, 25 (35%) were non-diabetics and 24 (33%) were not screened. Thirty patients were treated with intermittent HDS (median dose equivalent to prednisolone 160 mg) as part of their chemotherapy regimen or treatment. All 5 patients with known diabetes developed SIH, requiring a change of treatment. Nine of 25 (36%) non-diabetics also developed SIH requiring initiation of treatment. CBG levels progressively increased for some patients during successive cycles, suggesting monitoring should continue throughout treatment. CBG returned to baseline once steroids had been discontinued. There were no hypoglycaemia events. Two patients required hospital admission with SIH (1 not monitoring CBG, 1 with complications after allogeneic bone marrow transplant with coexisting CBGs between 20–25 mmol/l). SIH is common and clinically important, occurring in all patients with pre-existing diabetes and 36% of those without. The effects on ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

CBG are reversible. Our protocol was able to detect and manage SIH without causing hypoglycaemia. Patients and staff found the protocol acceptable and manageable.

158 Preliminary clinical experience on the efficacy and feasibility of a new combination regimen consisting of pixantrone (Pix), etoposide, and bendamustine with or without the addition of rituximab in patients with relapsed/refractory aggressive non-Hodgkin lymphomas (aNHL) F d0 Amore1, J Jørgensen1, I Sillesen1, E Segel1, H Bentzen1, M Thorsgaard1, EJ Pulczinsky1, BB Pedersen1, D Gillstroem1, €2, M Clausen1, P Kamper1, T Silkjaer1, L Gormsen1, S Leppa 1 3 3 3 HE Toldbod , M Turton , P Zintl , P Theocharous 1 Department of Hematology and Nuclear Medicine, Aarhus University Hospital, Denmark; 2Department of Oncology, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; 3CTI Life Sciences, Uxbridge, UK Aim was evaluating a combination based on pixantrone:novel azaanthracenedione EMA approved in multiply relapsed/refractory aNHL. Etoposide+bendamustine in prior combination with Pix showed efficacy in salvage regimens in relapsed/refractory aNHL. Schedule:Pixantrone 50 mg/m2 i.v. day1 + 8, Etoposide100 mg i.v. day1, Bendamustine90 mg i.v. day1 + /- Rituximab375 mg/m2 i.v. day1 (PREBEN/PEBEN). Each cycle was given at 3-weekly intervals for a maximum of 6 cycles. All patients were assessed with PET/CT after cycle 1 or 2. G-CSF support was administered according to guidelines. Results: 10patients with relapsed/refractory aNHL were treated according to the PREBEN/PEBEN-schedule and were evaluable in terms of presentation, feasibility and response. The histological diagnoses were distributed as follows: relapsed/refractoryDLBCL (N = 6), transformed follicular lymphoma (tFL;N = 2), post-transplant lymphoproliferative disease-DLBCL type (PTLD-DLBCL; N = 1), peripheral T-cell lymphoma (PTCL-NOS; N = 1; without rituximab). Based on PET/CT assessment performed already after 1course of treatment, the PREBEN/PEBEN regimen showed metabolic CR in 4/ 10patients (DLBCL; N = 4) and good PR in 3 patients (DLBCL; N = 1, tFL N = 1, PTCL-NOS=1) corresponding to ORR = 70% (CR:40%; PR:30%), no response in 3/10 pts (DLBCL = 1, PTLDDLBCL = 1, tFL = 1) (PD: 30%). In both CR and PR patients, a marked reduction of lesions was already detectable after the 1 course of treatment. RD was in the range 5–14+ months. The regimen was feasible and most patients received it as out-patients. Most common grade 3–4 toxicity was of hematological type. Grade 3–4 infections were seen in 40% of these heavily pretreated patient, but were manageable and could be successfully treated. Conclusion: The PREBEN/PEBEN schedule is feasible and profound responses early in the course of therapy are not uncommon. A phase 1 / phase 2 (extension) study is in preparation.


Poster Session: Lymphoid Malignancy – Clinical

159 Identifying MYC dysregulation in diffuse large B-cell lymphoma (DLBCL): correlation between immunohistochemistry (IHC) and fluorescencein-situ hybridisation (FISH) H Medani1, S Araf2, M Grantham3, M Calaminici1, H Rizvi1 1 Department of Cellular Pathology, Barts Health Specialist Integrated Haematology Malignancy Service (SIHMDS), Royal London Hospital, Barts Health NHS Trust, UK; 2 Department of Haemato-Oncology, St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK; 3Department of Molecular Pathology, Barts Health Specialist Integrated Haematology Malignancy Service (SIHMDS), Royal London Hospital, Barts Health NHS Trust, London, UK MYC dysregulation in diffuse large B-cell lymphoma (DLBCL) either as a stand-alone phenomenon or in combination with other oncogenes, commonly BCL2 (‘double-hit’ lymphoma) – indicates adverse prognosis with no established treatment paradigms. Fluorescence-in-situ-hybridisation (FISH) is the gold standard for detection of MYC translocation but this does not detect all genetic alterations leading to MYC dysregulation. The availability of a monoclonal antibody has allowed immunohistochemical (IHC) detection of MYC protein expression. In contrast to FISH, IHC detection is cheaper, technically less challenging and more widely available, thus providing an attractive alternative method to detect MYC dysregulation. While there is agreement on the technical performance, literature on the interpretative aspects of IHC detection shows wide variation with a range of 40–70% used as cut-off for overexpression. Clearly, instituting IHC detection of MYC in routine diagnostics requires validation and verification at each centre. We present our institutional experience in this retrospective analysis of 80 patients with DLBCL (with MYC IHC and FISH data), diagnosed and treated in our centre from January 2013-June 2014. Based on literature, we used a cut-off value of 50% (tumour nuclei, strongly positive for MYC) to define over-expression. Of the 80 patients, 38 (48%, 38/80) demonstrated MYC overexpression on IHC and 21 of these 38, demonstrated MYC rearrangement on FISH (55%, 21/38). There were no false negative IHC results. The false positive cases could be explained by alternative molecular alterations resulting in overexpression of MYC protein. Our study confirmed an IHC cut-off of 50% to be a robust, fast and inexpensive method of screening patients who warrant further FISH studies for risk stratification. This has led to a change in practise at our centre with all cases of DLBCL undergoing an initial MYC IHC screen followed by FISH studies for MYC, BCL2 and BCL6, if required.

160 Implementing a remote surveillance programme for lymphoma patients G Howard-Jones1, M Mulhall2, V Sankar2, M Hebbard2, A Davies2, A Bates3, F Forconi4, D Ayres3, A Richardson5, P Johnson2 1 NIHR Clinical Doctoral Research Fellow, Faculty Health Science, University of Southampton and Medical Oncology, University Hospital Southampton Foundation Trust, UK; 2 Medical Oncology, University Hospital Southampton Foundation Trust, Southampton, UK; 3Clinical Oncology, University Hospital Southampton Foundation Trust, Southampton, UK; 4Haematology, University Hospital Southampton, Southampton, UK; 5Faculty of Health Sciences, University of Southampton and Cancer Care, University Hospital Southampton Foundation Trust, Southampton, UK Introduction: 5 year survival rates of lymphoma patients continue to rise. With increasing numbers of patients in ongoing remission but in need of recurrence surveillance, clinics are frequently overwhelmed with large numbers of well patients. This is leading to poor patient experience and reduced service delivery effectiveness. In line with a programme developed by the National Cancer Survivorship Initiative and Macmillan, Patient Triggered Follow Up (PTFU) for lymphoma patients was implemented at Southampton. Methods: Engagement was sought with the Trust, contractors and commissioners for funding and pathway development. A successful bid for a Macmillan Support worker was made for ongoing management. Protocols were generated for 5 common lymphoma sub-types and a live data base created to monitor patients’ attendance and test results. 24 months from response assessment those patients who remained disease free or stable stopped traditional out-patient appointments, instead attending a self-management workshop and followed a programme of remote routine investigations monitored by the hospital team. New out-patient appointments were triggered by abnormal results or if patients had health concerns. Patients were notified of their results via an online account, post or telephone. Results: From October to 31 December 2014 85 patients had been screened for PTFU prior to clinic attendance. 53 (62%) enrolled in PTFU. Of 32 patients not enrolling only 3 (9%) patients declined participation. Remaining patients were ineligible due to; discharged from clinic 7 (21%), new lymphadenopathy 6 (18%), too many comorbidities 6 (18%), trial follow up 5 (15%), low social support 5 (15%). This has released approximately 212 routine follow up appointments over the next 24 months. Conclusions: PTFU offers a new approach to actively support the increasing numbers of lymphoma patients to self-manage their survivorship concerns, while releasing capacity to manage acute patients and improve service delivery outcomes for all.

161 Outcome for patients with relapsed/refractory lymphoma treated with gemcitabine and oxaliplatin with or without rituximab V Dhanapal1, L Chia1, R Marcus1, C Delord1, S Bowcock1, S Devereux1, P Patten1, D Yallop1, D Wrench2, P Fields2, S Kassam1 1 Kings College Hospital, UK; 2Guy’s & St Thomas’ Hospital, UK Relapsed/refractory aggressive lymphoma remains challenging to treat. There is no standard salvage chemotherapy regimen. Studies suggest that the outpatient combination of Gemcitabine, Oxaliplatin


ª 2015 Blackwell Publishing Ltd British Journal of Haematology, 169, (Suppl. 1), 1–104

Poster Session: Lymphoid Malignancy – Clinical (Gem-Ox) with Rituximab (R) achieves similar response rates (RR) with less toxicity than intensive inpatient regimens. This retrospective study reviews outcomes for patients treated with Gem-OxR at two London teaching hospitals. Twenty-four patients, 15 male, with a median age of 51 years (range 23–76) were treated between 2010 and 2014. Fifteen (63%) patients had DLBCL; 13 had received prior R. Six had T-cell lymphoma and 3 Hodgkin lymphoma. The median number of prior treatments was 1 (range 1– 6). Five patients had received an autologous transplant, 1 of whom had also received an allogeneic transplant. Remission duration (RD) to last treatment was 12 months compared to 0/16 patients whose prior RD was

Abstracts of the 55th Annual Scientific Meeting of the British Society for Haematology, 20-22 April 2015, Edinburgh, UK.

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