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Acute thrombotic thrombocytopenic purpura (TTP) is a life-threatening emergency and plasma exchange (PEX) is the initial treatment shown to reduce acute mortality.To compare current practice in the United Kingdom (UK) against the standards set out in the 2012 British Society of Haematology guideline, and to better understand the issues affecting prompt initiation of PEX.The trainee research network HaemSTAR conducted a retrospective nationwide review of adults presenting to UK hospitals with a first episode of acute TTP.Data on 148 patients treated at 80 UK hospitals between 2014 and 2019 demonstrated that 64.8% of patients received PEX within 24 h. Diagnostic uncertainty was the most commonly cited reason for delayed treatment. Conversely, a shorter time to PEX occurred in patients who had red cell fragments or severe thrombocytopenia identified on their first complete blood count. Availability of on-site PEX was associated with a greater proportion of patients receiving PEX within 8 h compared to patients transferred, but by 24 h there was no difference between the two groups and two-thirds of all patients had received their first PEX. The mortality rate for patients that received PEX was 9.2%, with 27.8% of deaths linked to delayed treatment initiation.This is the first multi-center evaluation of treatment delays in acute TTP and it will inform targeted pathways to improve prompt access to life-saving intervention.

PURPOSE Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

An increasing number of patients are being prescribed direct oral anticoagulants (DOACs), while the patients who remain on warfarin are becoming more complex. There is currently a lack of a standardised anticoagulation review for patients in primary care, resulting in potentially preventable harm events. Our aim was to implement a new service, where a standardised review is carried out by a specialist multidisciplinary secondary care anticoagulation team. Overall, the implementation of a standardised review resulted in better optimisation of anticoagulation management for patients taking either a DOAC or a warfarin. Of the 172 eligible patients prescribed warfarin, 47 (27%) chose to switch a DOAC. The average time in therapeutic range for patients on warfarin before and after the pilot increased from 73.5% to 75%. Of 482 patients taking a DOAC, 35 (7%) were found to be on incorrect dose. In 32 (91%) of 35 patients, the dose was amended after notifying the patient’s general practitioner. We also found a significant number of patients inappropriately prescribed concomitant medication such as antiplatelet or non-steroidal anti-inflammatory drugs, potentially putting the patients at an elevated risk of bleeding. While further research is needed; we believe the results of this pilot can be used to help build a case to influence the commissioning of anticoagulation services. Secondary care anticoagulation teams, like our own, may be well-placed to provide or support such services, by working across the primary care and secondary care interface to support our primary care colleagues.

Introduction: Waldenström's Macroglobulinaemia (WM) is a rare indolent B-cell lymphoma characterised by lymphoplasmacytic infiltrate with an IgM paraproteinaemia. Approximately 400 patients (pts) are diagnosed annually in the United Kingdom (UK). National and regional registries provide important insights on the epidemiology and clinical features of this distinct uncommon disorder. Previous authors from the United States have reported significant differences in age at diagnosis and overall survival (OS) in WM between ethnic groups from Surveillance, Epidemiology and End Results data [1]. We aimed to determine baseline demographics, symptoms and survival outcomes across different ethnic groups in the UK. Methods: We retrospectively reviewed data from the WMUK Rory Morrison Registry, collating descriptive data of WM as well as non-IgM Lymphoplasmacytic lymphoma (LPL) cases from 20 centres across the UK, diagnosed between June 1978 and May 2021. Research ethics approval was obtained. Results: 732 pts with documented ethnicity were included here. Ethnicity was categorised in accordance with the UK National Census. Those other than the White cohort (662/732; 90%) were collectively termed 'Ethnic Minorities' (EM) (70/732; 9%): 39/70 (56%) Asian (13 Indian, 6 Chinese, 4 Pakistani, 16 other); 19/70 (27%) Mixed (1 White & Black African, 1 White & Asian, 1 Arab, 16 other); 12/70 (17%) Black (6 Caribbean, 3 African, 3 other). Baseline characteristics are displayed in table 1. EM presented at a significantly younger age compared to White cohort (60 vs 64 years, p=0.01) and had a significantly lower paraprotein at diagnosis (11 vs 18g/L, p=0.05). MYD88 L265P mutation tested in 250 pts (34%): positive in the majority 218/250 (87%) and notably less common in EM (p=0.09), most significantly in the Asian cohort compared to White (67% v 88%, p=0.01). The EM cohort had a smaller proportion of WM diagnoses compared to White cohort (77% vs 93%, p=0.02) with the Asian cohort accounting for the highest proportion of non-IgM LPL (15% vs 4%, p=0.002). Bone marrow trephine infiltration at diagnosis was lower in the EM cohort compared to the White cohort, although not statistically significant (25% vs 37%, respectively; p=0.10). IPSSWM scores were similar throughout. Approximately half of both the White & EM cohorts were asymptomatic at diagnosis. The most common presenting symptoms in EM were anaemia-related (10/34; 29%), B symptoms (6/34; 18%) and fatigue (4/34; 12%). 6/18 (33%) of Asians presented with cryoglobulinaemia, amyloid, nephropathy or acquired von Willebrand's Disease. Of EM, 51/70 (73%) had treatment, 35/51 (69%) within the first year from diagnosis with time to treatment 2 months (range 0-364). Time to next therapy was 14 months. Median lines of therapy were 2 (range 1-8). The most common indication for first line therapy was lymphoma-related (16/39; 41%) followed by paraprotein-related (peripheral neuropathy, hyperviscosity and autoimmune) (13/39; 33%). First line therapies included Bendamustine-Rituximab (BR; 8/49; 16%), Dexamethasone Rituximab Cyclophosphamide (DRC; 7/49; 14%) and R-CHOP (5/49; 10%) with smaller proportions receiving Rituximab monotherapy, Cladribine + Rituximab or Fludarabine + Cyclophosphamide + Rituximab (FCR) (3/49 (6.1% each). Two of 41 (5%) of EM had first treatment as a part of a clinical trial, compared to 16/156 (10%) of the White cohort (p=0.28). Response to first line therapy was similar between the White & EM cohorts (Table 1). For EM, at a median follow up of 7 years, 17 died (1/17; 6% disease related). Median OS was not reached (Figure 1). Estimated 5-year and 10- year OS was 91% (95% CI 96-80%) and 75% (95% CI 85-60%), respectively. Conclusions: This first report on ethnic disparities in WM and non-IgM LPL in the UK identified key differences in presentation of disease. Ethnic minorities present at a younger age, with a lower paraprotein. The Asian cohort had a greater proportion of non-IgM LPL cases and fewer MYD88 mutated cases. A small proportion of Ethnic Minorities have treatment on a clinical trial which may warrant further attention. Further analysis including associations with socioeconomic status, deprivation indices and comorbidities are ongoing. Ailawadhi, Sikander et al. "Outcome disparities among ethnic subgroups of Waldenström's macroglobulinemia: a population-based study." Oncology vol. 86,5-6 (2014): 253-62. doi:10.1159/000360992 Disclosures McCarthy: Janssen: Honoraria; Astra zenica pharmaceuticals: Honoraria; Amgen: Honoraria. Pratt: Amgen: Consultancy; Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy. El-Sharkawi: AbbVie: Honoraria, Other: Travel Support, Ad boards; AstraZeneca: Honoraria, Other: Ad boards; Janssen: Honoraria, Other: Ad boards; Roche: Honoraria; Takeda: Honoraria; Novartis: Other: Travel Support; ASTEX: Other: Ad boards; Beigene: Other: Ad boards; Kyowa Kirin: Other: Ad boards. Linton: Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Hartley Taylor: Honoraria; Celgene: Research Funding; BeiGene: Research Funding; University of Manchester: Current Employment. Gatto: Roche: Consultancy. D'Sa: Janssen Cilag: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Sanofi: Honoraria.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Now is an exciting time to be a mathematics teacher. The field is constantly changing. Nothing is sacred—not materials, not methods, not forms of assessment. Such drastic change, however, necessitates serious and extensive time for teachers to reflect on their own teaching and to become comfortable with new ideas and approaches (Joyce and Showers 1981, 1982; Schon 1983; Stallings 1989).

A major challenge in modern myeloma management is the selection of the best initial treatment from a plethora of available therapies. PAD (bortezomib, doxorubicin, and dexamethasone) is a highly effective regimen which may obviate the need for an upfront high-dose melphalan stem cell transplant (HDSCT). However, it is not clear a priori which patients will benefit from this treatment. In the phase 2 PADIMAC trial, patients with newly diagnosed myeloma were treated with six cycles of PAD and stratified to receive HDSCT in partial remission (PR) or watch and wait in very good partial remission (VGPR) or better. To identify predictive biomarkers, we extracted somatic RNA prior to treatment and performed massively parallel RNA sequencing (RNAseq). Basic quality control metrics suggested a high-quality RNAseq dataset. Furthermore, spiked expression of IgH fusion partners was consistent with fluorescent in situ hybridization (FISH) data for each sample. All t(4;14) and t(4;16) cases were correctly identified by RNAseq on the basis of the relevant fusion transcript. As a final quality control measure, recurrent variants (e.g. NRAS, KRAS, TP53, FAM46C, DIS3) were identified in the expected proportions. We performed a pre-planned analysis of differential gene expression between those patients achieving a VGPR or better, sustained for at least 12 months without HDSCT (excellent responders), and those patients who achieved less than a PR (poor responders). 85 genes were upregulated in poor responders and 225 in excellent responders. Interestingly, there was no significant overlap between our PAD-predictive signature and the Arkansas 70 gene poor prognosis signature, the Arkansas 17 gene poor prognosis signature, or the EMC92 prognostic signature. This is likely to reflect in part, the greater sensitivity of RNAseq for gene expression compared to microarrays. However, it also implies that there is a selective signature for PAD responsiveness. We employed the Gage and Pathview packages to identify non-redundant pathways associated with PAD responsiveness. Significantly upregulated genes in poor responders were those involved in: DNA replication, base excision repair, and the Fanconi anaemia pathway. Genes upregulated in excellent responders included those involved in: several signalling pathways (including RAS, NF-Kappa B, FOXO and JAK-STAT pathways); chemokine and cell adhesion; protein processing in the endoplasmic reticulum; and immune activation pathways such as T-cell receptor signalling and natural killer cell-mediated cytotoxicity. Finally, we investigated the ability of expression signatures to stratify patients on the basis of PAD responsiveness. Our analysis suggests that RNASeq-defined transcriptional profiles could aid in the selection of patients for PAD therapy (leading to an increase in overall response rate from 70% to 86%), as well as the stratification of patients in CR to a non-HDSCT protocol. We anticipate that our current analysis could easily incorporate specific response signatures for other regimens and could make personalized therapy for myeloma a reality in the foreseeable future. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Streetly:Guys and St. Thomas' NHS Trust: Honoraria. Schey:Celgene, Takeda: Honoraria; Celgene: Consultancy; Celgene, Johnson & Johnson: Speakers Bureau. Cook:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria. Cook:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Myeloma UK: Membership on an entity's Board of Directors or advisory committees.

A significant incidence of post-procedural deep vein thrombosis (DVT) and pulmonary embolus (PE) was identified in patients undergoing surgery at our hospital. Investigation showed an unreliable peri-operative process leading to patients receiving incorrect or missed venous thromboembolism (VTE) prophylaxis. The Trust had previously participated in a project funded by the Health Foundation using the "Safer Clinical Systems" methodology to assess, diagnose, appraise options, and implement interventions to improve a high risk medication pathway. We applied the methodology from that study to this cohort of patients demonstrating that the same approach could be applied in a different context. Interventions were linked to the greatest hazards and risks identified during the diagnostic phase. This showed that many surgical elective patients had no VTE risk assessment completed pre-operatively, leading to missed or delayed doses of VTE prophylaxis post-operatively. Collaborative work with stakeholders led to the development of a new process to ensure completion of the VTE risk assessment prior to surgery, which was implemented using the Model for Improvement methodology. The process was supported by the inclusion of a VTE check in the Sign Out element of the WHO Surgical Safety Checklist at the end of surgery, which also ensured that appropriate prophylaxis was prescribed. A standardised operation note including the post-operative VTE plan will be implemented in the near future. At the end of the project VTE risk assessments were completed for 100% of elective surgical patients on admission, compared with 40% in the baseline data. Baseline data also revealed that processes for chemical and mechanical prophylaxis were not reliable. Hospital wide interventions included standardisation of mechanical prophylaxis devices and anti-thromboembolic stockings (resulting in a cost saving of £52,000), and a Trust wide awareness and education programme. The education included increased emphasis on use of mechanical prophylaxis when chemical prophylaxis was contraindicated. VTE guidelines were also included in the existing junior Doctor guideline App. and a "CLOTS" anticoagulation webpage was developed and published on the hospital intranet. The improvement in VTE processes resulted in an 80% reduction in hospital associated thrombosis following surgery from 0.2% in January 2014 to 0.04% in December 2015 and a reduction in the number of all hospital associated VTE from a baseline median of 9 per month as of January 2014 to a median of 1 per month by December 2015.

The National Institute for Health and Care Excellence (NICE) recommends integration of haematology and specialist palliative care (SPC) services in haematological malignancies, including SPC representation on the multidisciplinary team (MDT) (NICE 2003, Improving outcomes in haematological cancers: the manual , NICE, London). However, systematic reviews and meta-analyses reveal that patients with haematological malignancies are half as likely to receive SPC input as those with other cancers, and twice as likely to die in hospital, where death is associated with lack of SPC referral (Howell et al . 2014, ‘Variations in SPC referrals...’, BMJ Supportive and Palliative Care ; 0: 1–7). Might these findings relate to gaps in palliative care education within haematology specialty training? To address this, four first-year haematology trainees were offered placements at the local hospice. Their programme included: the Inpatient Unit (MDT meetings, ward rounds, tutorials, observing SPC doctors consulting and admitting patients for symptom control, respite and terminal care); Day-patient Unit; Family Support Team; Chaplaincy; and community work (accompanying Nurse Specialists at caseload reviews, home visits and GP surgeries). Pre- and post-placement, the trainees rated their ability to: break bad news; empathise with patients; provide symptom control; and discuss prognosis with relatives. For each trainee, confidence in each skill-set improved. Individual learning objectives were co-constructed with the lead clinician and reviewed post-placement. Each trainee wrote post-placement reflections on personal and professional perspectives of care. Theserevealed insights into barriers to referral from haematology to SPC services, and ways of overcoming these. Although palliative care lies within the JRCPTB haematology syllabus,with evidence of engagement through case based discussions and mini-clinical evaluation exercises requested, these were electronically impossible to upload until this work was presented. We highlight current gaps in palliative care education within haematology training, and recommend that formal palliative care education through hospice placements may enhance patient outcomes and experiences in haematological malignancies.

Introduction: The role of autologous stem cell transplantation (ASCT) as first line treatment for newly diagnosed patients with myeloma is currently under evaluation given the high response rates to novel induction treatment. The outcomes for patients that do not proceed to ASCT following induction remain unclear and are likely to be determined by genetic risk and response to therapy. In order to evaluate this further, this single arm phase 2 clinical trial conducted at 13 sites in the UK was designed to determine the 2 year progression free survival for patients that achieved ≥ very good partial response (VGPR) following induction therapy without ASCT. Those achieving partial response (PR) were consolidated with ASCT according to routine practice. In this first analysis we report secondary endpoints: disease response and regimen-related toxicity in patients completing induction, including minimal residual disease (MRD) negativity by multiparameter flow cytometry. Methods: Patients with newly diagnosed myeloma eligible for ASCT received PAD (bortezomib 1.3mg/m2 days 1, 4, 8, 11; doxorubicin 9mg/m2 days 1-4 and dexamethasone 40mg days 1-4 (and days 8-11 and 15-18 for the first cycle only)) for up to 6 cycles (minimum of 4). Bortezomib was initially given intravenously (IV), but once approved this was switched to sub-cutaneous (SC). Those failing to achieve PR were offered salvage therapy off protocol. All others had peripheral blood stem cell (PBSC) mobilisation using cyclophosphamide + GCSF, followed by MRD assessment on bone marrow aspirates using multi-parameter flow cytometry. Depending on disease response, patients were then stratified to ASCT (PR) or no further treatment (≥VGPR). Responses were assessed using International uniform response criteria (Durie 2006) by intent-to-treat and toxicity scored according to CTCAE version 4.0. High risk disease was defined by the presence of one or more adverse FISH lesions (t(4;14), t(14;16), t(14;20), del(17p13), +1q21) as described in the MRC Myeloma IX trial. Results: Between March 2011 and January 2014, 153 patients were enrolled (median age of 55, range 28-71 years). 139 (91%) received between 4-6 cycles of PAD. The majority (135, 88%) received SC only bortezomib and 18 (12%) received at least 1 cycle IV. The overall response rate to PAD was 81% with 46% achieving ≥VGPR (sCR: 6 (4%), CR: 13 (8%), VGPR: 51 (33%), PR: 54 (35%)). FISH data was available for 122 patients, 91 (75%) patients were standard risk and 31 (25%) were adverse. Responses were similar irrespective of ISS or genetic risk (standard, ≥VGPR 44%, PR 34%; adverse, ≥VGPR 55%, PR 29%). MRD results are currently available in 70 of the 124 patients achieving PR post PBSC harvest. Of this group 41 achieved ≥VGPR post-harvest (22 MRD+ and 19 MRD-) and hence did not proceed to ASCT, 13 patients achieved CR of which 8 were MRD negative. Toxicity was as expected for PAD and predominantly haematological. Notably the incidence of neuropathy was lower than that previously reported with IV bortezomib. Grade 3-4 events were: neutropenia: 18%; thrombocytopenia 7%. Grade 2-4 peripheral neuropathy was reported in 27% compared to 40% in the HOVON-65/ GMMG-HD4 Trial using IV bortezomib. Grade 1-2 neuropathy was similar for patients who received IV (55.6%) or SC (60%) bortezomib; however only 7% of patients receiving SC bortezomib developed grade 3 neuropathy compared to 28% with the IV route. Conclusions: SC PAD is a highly effective induction regimen for patients with newly diagnosed myeloma achieving a ≥VGPR of 46%. Of the 41 patients achieving ≥VGPR post-harvest with MRD result available, 46% were MRD negative. Response rates were similar across ISS and with adverse FISH. The use of SC bortezomib improved tolerability and substantially reduced neurotoxicity. ISRCTN no: 03381785. Disclosures Popat: Janssen: Honoraria. Cavenagh:Janssen: Honoraria. Schey:Janssen: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cook:Janssen: Honoraria, Research Funding. Yong:Janssen: Honoraria.