Search

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.

Primary central nervous system lymphoma is rare, comprising 4% of intracranial neoplasms. Although haematologists or oncologists subsequently manage the condition, it is often neurologists who first make, or at least suspect, the diagnosis. This article reviews the disease, its clinical and radiological features and details the work-up needed to achieve a diagnosis (namely histological or cytological confirmation) and to prepare the patient for treatment. We note the importance of brain biopsy, the role of corticosteroids and the varied treatment options.

Funder: Janssen Pharmaceuticals; Id: http://dx.doi.org/10.13039/100008897, Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.

Background: Acute Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening medical emergency and plasma exchange (PEX) is the only treatment shown to significantly impact acute mortality (Rock et al, N Engl J Med 1991). Diagnosis can be challenging and therein arrangements for PEX must be made, with most centers in the United Kingdom (UK) having to co-ordinate transfer to a tertiary site. To understand issues affecting practice the trainee research network HaemSTAR conducted a retrospective nationwide review of patients presenting to UK hospitals with TTP against British Society of Haematology clinical guidelines (Scully et al, B J Haem 2012). Analysis was conducted on the time from hospital presentation to initiation of treatment and impact on patient outcomes. Method: Adults ≥18 years presenting to hospital between 1st June 2014 and 1st June 2019 with first episode acute TTP and ADAMTS13 level Results: Data on 148 patients treated at 80 UK hospitals was used for analysis (demographics table 1). 142 patients (96%) received PEX, 67 (47%) at site of presentation and 75 (53%) after hospital transfer. 6 patients died before receiving PEX. 37 patients (25%) received PEX within 8 hrs of hospital presentation, 91 patients (61%) within 24 hrs. 33 patients (22%) commenced PEX more than 48 hrs from presentation. The overall median time to PEX from initial presentation was 15 hours (95% CI 11.3-18.7). Availability of on-site PEX was associated with earlier treatment initiation with median time to PEX for those treated on site 10 hrs (95% CI 7.7-12.3) vs. 21 hrs (95% CI 16.8-25.2) for patients transferred. A blood film comment of red cell fragments significantly impacted time to treatment: in 24 cases with no fragments documented median time to PEX was 110 hrs (95% CI 39-181) vs. 10 hrs (95% CI 8.5-11.5) in cases where fragments were reported (fig 1). On univariate and multivariate analysis age 96 patients (62%) received steroids within 24 hrs of presentation, 98 of 128 patients with cardiac/CNS involvement (77%) received rituximab within 48 hrs and 12 patients (8%) received platelet transfusion in the absence of major bleeding. 19 patients (12%) died within 30 days of presentation (median time to death 10 days, range 0-23). In 7 of these cases (37%) a delay >24 hrs from presentation to diagnosis was reported despite presence of fragments in 4 cases. Mortality did not correlate with availability of on-site PEX. Discussion: This is the first multi-center record of time to treatment from initial presentation of acute TTP. Results comply with guidance for rapid initiation of PEX with 61% patients commencing within 24 hrs of presentation and, from June 2017, 34% of patients initiating PEX within 8 hrs. The recent increase in early PEX initiation correlates with initiatives to improve treatment pathway efficiency following diagnosis of TTP. Early use of steroids and rituximab correlated with earlier use of PEX indicating where timely diagnosis was made there was good compliance with guidelines. Inappropriate use of platelets appeared attributable to misdiagnosis. Older patients, those with higher platelet counts and Hb and absence of red cell fragments on film report were more likely to experience prolonged time to initiation of PEX. This does not appear related to PEX access, but most likely the difficulty of making TTP diagnosis in this cohort. That 22% of patients initiated PEX over 48 hrs from admission indicates the issue is relatively common and with several deaths occurring in this group we suggest initiatives to increase early diagnosis should be prioritised. Full contributor list: http://haemstar.org/flash-mob-audit-2019/ Disclosures McCulloch: Sanofi: Research Funding. Nicolson:Principia Biopharma: Research Funding; Novartis: Research Funding; Rigel pharmaceuticals: Research Funding; Bayer: Honoraria. Shaw:Octapharma: Research Funding. Scully:Alexion: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau.

Patients with mantle cell lymphoma (MCL) that fail induction treatment represent a difficult-to-treat population, where no standard therapy exists. We evaluated outcomes in patients with first relapsed-refractory (r/r) MCL after upfront high dose cytarabine including standard regimens. Overall survival (OS-2) and progression-free survival (PFS-2) were estimated from the time of salvage therapy. The previously described threshold of 24 months was used to define patients as early- or late-progressors (POD). Overall, 261 r/r MCL patients were included. Second-line regimens consisted of rituximab-bendamustine (R-B, 21%), R-B and cytarabine (R-BAC, 29%), ibrutinib (19%), and others (31%). The four groups were balanced in terms of clinicopathological features. Adjusting for age and early/late-POD, patients treated with R-BAC had significantly higher complete remission (63%) than comparators. Overall, Ibrutinib and R-BAC were associated with improved median PFS-2 [24 and 25 months, respectively], compared to R-B (13) or others (7). In patients with early-POD (n = 127), ibrutinib was associated with inferior risk of death than comparators (HR 2.41 for R-B, 2.17 for others, 2.78 for R-BAC). In patients with late-POD (n = 134), no significant differences were observed between ibrutinib and bendamustine-based treatments. Ibrutinib was associated with improved outcome in early-POD patients.

Ibrutinib, obinutuzumab, and venetoclax demonstrate synergy in preclinical models of mantle cell lymphoma (MCL). OAsIs (NCT02558816), a single-arm multicenter prospective phase 1/2 trial, aimed to determine the maximum tolerated dose of venetoclax in combination with fixed doses of ibrutinib and obinutuzumab, in relapsed MCL patients. At the venetoclax MTD, extension cohorts were opened for relapsed and untreated patients. Safety and efficacy were secondary objectives. Minimal residual disease (MRD) was assessed by allele-specific oligonucleotide quantitative polymerase chain reaction. Between 14 October 2015 and 29 May 2018, 48 patients were enrolled. No dose-limiting toxicity was reported, and venetoclax at 400 mg per day was chosen for extension. Eighteen (75%) relapsed and 8 (53%) untreated patients experienced grade 3/4 adverse events. The complete response rate assessed by positron emission tomography at the end of cycle 6 was 67% in relapsed and 86.6% in untreated patients. MRD clearance for evaluable patients was seen in 71.5% of relapsed (10/14 patients) and 100% of untreated MRD-evaluable patients (n = 12) at the end of 3 cycles. The median follow-up for relapsed patients was 17 months (range, 10-35 months). The 2-year progression-free survival (PFS) was 69.5% (95% confidence interval [CI], 52.9%-91.4%) and 68.6% (95% CI, 49.5%-95.1%) for overall survival. The median follow-up was 14 months (range, 5-19) for untreated patients, the 1-year PFS was 93.3% (95% CI, 81.5%-100%). The combination of obinutuzumab, ibrutinib, and venetoclax is well tolerated and provides high response rates, including at the molecular level, in relapsed and untreated MCL patients. This trial was registered at www.clinicaltrials.gov as #NCT02558816.

Patients with mantle cell lymphoma progressing on Bruton's tyrosine kinase inhibitor (BTKi) have very poor prognosis and there is currently no standard of care. In this retrospective cohort study, patients progressing on BTKi received R-BAC (rituximab, bendamustine, cytarabine). Overall response rate was 83% (complete response 60%) and 31% were bridged to allogeneic stem cell transplant (alloSCT). Median progression-free survival was 10.1 months (95% confidence interval (CI) 6·9-13·3) and median overall survival was 12·5 months (95% CI 11·0-14·0). In those consolidated with alloSCT only one patient relapsed. R-BAC demonstrates a high response rate in the post-BTKi setting and in transplant eligible patients is an effective bridge to alloSCT.

Intravenous immunoglobulin (IVIg) is a common therapy for patients with immune thrombocytopenia (ITP). The initial response rate for IVIg is 80%[1][1] and is typically rapid, with some patients responding in 24 hours, although usually in 2–4 days.[2][2] When IVIg is used alone, the response is

Background Effective treatment for relapsed, refractory (R/R) mantle cell lymphoma (MCL) post Bruton's Tyrosine Kinase inhibitor (BTKi) therapy represents an unmet clinical need with studies consistently reporting dismal outcome. No treatment strategy demonstrates superiority and there is currently no consensus on management. R-BAC (Rituximab, Bendamustine and Cytarabine) has demonstrated excellent upfront response rates in phase 2 trials (overall response rate (ORR) 100%, 2-year progression free survival (PFS) 95%, Visco et al 2013), but with durable responses also reported with other combination therapies there is a rationale to reserve R-BAC for post-BTKi relapse. Aims There is currently no data available assessing efficacy of R-BAC in the post BTKi setting. We first adopted this treatment strategy within routine clinical practice in 2015 and in this study have collected and analysed clinical outcomes across 20 centers in the United Kingdom and Italy. Methods 35 R/R MCL patients (pts) with prior BTKi therapy started R-BAC between October 2015 and February 2019. Treatment consisted of rituximab (375 mg/m2 or 500 mg) D1, bendamustine 70 mg/m2 D1 and D2 and cytarabine 500 mg/m2 D1 to D3 in a 28 day cycle. 29 pts were treated in the UK and 6 in Italy. Analysis included one pt with previous alloHSCT. Response to therapy was measured using Lugano classification (Cheson et al, 2014), although assessment of CR with bone marrow biopsy was not always undertaken. Baseline data, including response to previous BTKi, was collected retrospectively by the treating physician. The primary outcome was PFS to R-BAC. Results Median age at time of R-BAC was 66.3 years (range 43 to 81) and 82.9% of pts were male. At initial diagnosis MIPI was 34.5% low risk, 17.2% intermediate risk and 48.3% high risk; histology was 20.6% blastoid. Pts received a median 2 prior lines of systemic therapy (range 1 to 6). Frontline therapy included high dose cytarabine containing regimen (61.7%) plus consolidation AutoSCT (40.0%), R-CHOP (26.4%), R-CVP (2.9%), FC (2.9%) and ibrutinib plus rituximab (5.9%). 7 patients received maintenance rituximab (28.6%). 45.7% of patients commenced second line therapy within 2 years of initial diagnosis. Prior BTKi therapy included: ibrutinib (n=30), acalabrutinib (n=2), tirabrutinib (n=2) and M7583 (n=1). ORR to prior BTKi was 67.6% (CR 35.3%) and median PFS was 9.2 months. All patients stopped BTKi therapy due to progressive disease (94.3%) or failure to respond (5.7%). All but 1 patient received R-BAC directly after relapse on BTKi. Patients received a median of 4 cycles of treatment (range 1 to 6). 9 pts received attenuated doses of chemotherapy at clinician's discretion from start of therapy and 13 additional pts received attenuated doses beyond cycle 1 (62.9% of all patients received some form of dose attenuation). ORR to R-BAC was 82.3% (CR/CRu rate 55.9%), median PFS 9.3 months (see fig. 1) and median OS 12.2 months. Importantly, outcome for 11 pts ≥70 yrs was similar to younger pts (median PFS 10.6 months vs 8.6 months, p=0.83). 53.5% of evaluable patients demonstrated longer duration of response compared with preceding BTKi. 25 pts completed the planned treatment course, 2 stopped early due to excess toxicity (prolonged cytopenias and infection) and 8 stopped early due to progressive disease. 9 pts received subsequent consolidation alloSCT, and 1 DLI. Although follow-up is short only 1 patient to receive alloSCT has relapsed. 13 patients overall remain in remission, including 5 beyond 12 months. 18 patients (51.4%) required admission during R-BAC, including 15 with neutropenic fever (42.8%) and 72.7% patients required transfusion support. There were no treatment related mortalities. Conclusion This high risk population with a short PFS to prior BTKi demonstrated an excellent response rate to R-BAC. Favorable outcomes in the cohort consolidated with alloSCT, and the generally short duration of response in other pts, suggests R-BAC can be primarily used as a bridge to alloSCT in suitable pts. Treatment had notable hematological toxicity but with efficacy maintained in older pts R-BAC remains a valid option in those deemed unsuitable for transplant, although judicious dose attenuation is advised. In an area lacking a clear therapeutic path, the results from our study support R-BAC being considered a new standard of care option for R/R MCL in the post BTK inhibitor setting. Disclosures Frewin: AbbVie: Other: Meeting attendance sponsorship ; Novartis: Consultancy, Other: Meeting attendance sponsorship . Eyre:Roche: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Janssen: Honoraria. Lambert:Takeda Pharmaceuticals: Other: Funding to attend a scientific conference in 2018. Crosbie:Janssen: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy.

Background. Novel targeted therapies have demonstrated high efficacy in relapse and/or refractory (R/R) MCL. Ibrutinib, a first in class BTK inhibitor, is approved for R/R MCL. Venetoclax, a first in class bcl-2 inhibitor, is currently under investigation in prospective trials in R/R MCL. Obinutuzumab is a type II glycol-engineered, humanized anti-CD20 antibody approved in frontline and R/R follicular lymphoma which has shown efficacy in MCL (Chiron Blood 2016, Le Gouill ICML/EHA 2019). Pre-clinical investigations have demonstrated the utility of combining these three molecules in MCL (Chiron et al, Blood 2016) The OAsIs trial (NCT02558816) is a multicenter, non-randomised, phase I study that was designed to assess the safety, tolerability and efficacy of Ibrutinib/ Venetoclax/Obinutuzumab in both R/R MCL and in newly diagnosed MCL. The study is divided into three steps (A, B,C, respectively) : step A enrolled nine R/R MCL who were treated with Ibrutinib plus Obinutuzumab and step B enrolled 24 R/R MCL patients who were treated with Ibrutinib/Venetoclax/Obinutuzumab (Venetoclax dose from 200 to 800mg ). The Ibrutinib/Venetoclax/Obinutuzumab combination demonstrated a good safety profile and high response rates in R/R MCL (step B). No DLT was reported in either step (Le Gouill et al, ASH 2018). Herein, we present the safety (primary objective), clinical and MRD results for Oasis step C where Ibrutinib/Venetoclax/Obinutuzumab was given to newly-diagnosed, untreated MCL patients. Methods: Obinutuzumab was given at 1000mg IV C1D1, 8, 15, C2-6 D1 and every 2 months until C23. Ibrutinib was given as a standard dose (560mg/d) from C1D2 and until progression. The dose of Venetoclax was 400mg (according to step B analysis and DSMC recommendations) and administered from C1-bis (to prevent TLS: C1-bis W1-20mg, C1-bis W2-50, C1-bis W3-100, C1-bis W4-200) and at 400mg from C2 to C23. Response was assessed by cheson 99 criteria at C2, C4 and C6 and by Lugano criteria at Cycle 6. MRD by ASO-qPCR (assay sensitivity 10-5) was measured at the end of C3 and 6 in blood and / or bone marrow. DLTs were assessed during the first 3 months (C1, C1-bis and C2) of treatment. Results. Fifteen untreated MCL patients were enrolled from August 2018 to April 2019, in 6 participating centers (France and UK). Median age at inclusion was 65y (range 51-77). All patients presented with stage III/IV disease and nodal disease (four patients had tumor mass >5cm). The MIPI score was high in 9 cases, intermediate in 5 and low in one case. One patient presented with pleomorphic variant. TP53 status at diagnosis was assessed in 13 patients (one was not informative and two are ongoing) of these one presented TP53 mutation. IGHV status (assessed in 13 patients, ongoing in 2) was mutated in two cases including the p53mutcase and not mutated in 8 (not informative in 3 cases). During the first three months of treatment (C1, C1-bis and C2), the relative dose intensity (ratio of delivered to the planned dose intensity) was 87% for Ibrutinib, 93% for Obinutuzumab and 100% for Venetoclax. During this period, non-hematological grade 3-4 AEs were hepatobiliary disorders (n=4; 3 patients with raised GGT-grade 3-, alanine -grade 3- and aspartate -grade 4- aminotransferase and one with biological cytolysis - grade 4) and rash (n=1; grade 3). Hematological grade 3-4 AEs were lymphocytosis (n=1; grade 3) and neutropenia (n=1; grade 4). All (n=15) patients are in response (including CR/uCR in 7 cases) at end of cycle 2 according to Cheson 99 criteria. In terms of MRD status, 8 patients (others are ongoing) were assessed at end of cycle 3 and all were MRD negative in BM (n=6) and/or in blood (n=8), including the p53mutpatient. Seven patients completed 6 cycles, all reached CR according to Lugano criteria (6 in CR/Cru according to Cheson criteria) and were MRD neg (in blood in all cases and in BM in 6 cases -one not done), including the P53mut patient. At date of last monitoring (Jul 2019), no disease progression is reported and all patients remain under the planned treatment. Conclusion. Ibrutinib/Venetoclax/Obinutuzumab combination therapy has a very good safety profile and shows high efficacity rates at the molecular level in untreated patients. Oasis step C is the first trial that report the use of Ibrutinib/Venetoclax/Obinutuzumab as frontline therapy in MCL. Disclosures Le Gouill: Janssen-cilag: Consultancy, Honoraria; Novartis: Consultancy; Abbvie: Consultancy, Honoraria; Roche Genentech: Consultancy, Honoraria; Gilead-Kite: Consultancy, Honoraria; Servier: Consultancy; loxo: Consultancy, Honoraria; Takeda: Consultancy. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Napp: Consultancy; TG Therapeutics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy. OffLabel Disclosure: Venetoclax, obinutuzumab in mantle cell lymphoma

Background: Although typically an aggressive disease some patients with Mantle Cell Lymphoma (MCL) follow an indolent course and may not benefit from immediate therapy. Several studies evaluating watch-and-wait (W&W) strategies in MCL show no detriment to patient survival and international guidelines acknowledge the strategy's suitability for a minority of patients. Differences in pathogenetic mechanisms have provided insight into variable clinical behaviour, but there is little clinical evidence to inform patient suitability for W&W. The MCL Biobank Observational Study is a prospective study designed to distinguish indolent from aggressive forms of MCL. Tissue samples and baseline characteristics are collected at enrolment. The study has recruited over 550 patients across the UK and remains open to recruitment. Method: This analysis includes 315 patients from 58 centers in the United Kingdom enrolled between January 2015 and March 2018. All new MCL diagnoses compatible with WHO diagnostic criteria were eligible. Patients were enrolled within 90 days of diagnosis and prior to receiving therapy. Baseline data was recorded including investigator decision to start systemic therapy or enter W&W. Clinical updates were provided at 6 month intervals and patients were followed-up for a minimum of 12 months. Standard statistical methods were used to examine which factors were associated with initial disease management and those remaining on W&W long-term. Time to treatment was measured from date of diagnosis until date of first treatment, patients who had not commenced treatment were censored at the last date of follow-up. Results: Median age of all patients was 71 (range 32-92), 68.9% were male, 53.5% were MIPI high risk and median follow up 26 months. At baseline 67.3% of patients received upfront systemic therapy, 4.1% received localized radiotherapy, 1.0% were palliated and 27.6% were on W&W 90 days beyond diagnosis. Estimated 2-year OS of the whole population was 77.5%. Patients on initial W&W tended to be older than those treated early (median 73 yrs vs. 71 yrs), had similar performance score (ECOG>1 OR 1.16, p=0.68) and no significant difference in WBC (WBC>15 OR 0.55, p=0.07). Although high risk MIPI was equally prevalent between the groups (OR 1.3, p=0.31) it was notable that no patient under 75 years was high risk in the observation group. Presence of measurable disease on CT discriminated between the two groups (OR 0.23, p= Of 87 patients followed on W&W 73.5% remained on observation at 1 year and 50.6% at 2 years, with median follow up 2.4 years. Univariate analysis revealed few baseline characteristics to be predictive for prolonged period of observation, in part relating to the low patient numbers, but key observations are displayed in figure 1. Patients with Ki67≥30% were less likely to remain on observation (HR 2.39, p=0.03), as were patients over 80 years old (HR 3.67, p=0.007), and those MIPI high risk compared to low risk (3.56, p=0.02). Conclusion: This study demonstrates the high prevalence of W&W in UK clinical practice and it provides reassurance to clinicians that half remain on observation beyond 2 yrs. LDH level and Ki67 status reflect the biological nature of disease and it is therefore not unexpected that lower levels predict for a more indolent course. However, with Ki67≥30 in 25% of patients observed beyond 2 years these measures alone are not sufficient to decide treatment. The tendency for older patients to be observed likely reflects a less aggressive clinical approach in patients with co-morbidities, and not the underlying biology. This explains the tendency for shortened observation period in older patients. The high prevalence of female patients in W&W is a striking observation that alludes to pathophysiological differences between the sexes that warrants further investigation. Although the study highlights clinicians are increasingly at ease adopting W&W in MCL, it also demonstrates the need for better predictive markers of indolent disease. This study aims to achieve this with analysis of the collected tissue samples. Disclosures Crosbie: Janssen: Honoraria. Rule:Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy; Gilead: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

Background: Ibrutinib has transformed the clinical approach to relapsed mantle cell lymphoma (MCL) with those receiving ibrutinib at first relapse obtaining the greatest benefit encouraging use earlier in the treatment algorithm (Rule et al, 2019). However, the general applicability of clinical trial findings is not established and concerns regarding ibrutinib tolerability persist, especially in non-trial populations enriched for frailer patients with multiple co-morbidities. In the United Kingdom, ibrutinib is funded as standard of care at first relapse. This study has analysed the clinical effectiveness and tolerability of this approach in a non-clinical trial real world population. Method: 23 centres across the United Kingdom contributed data from consecutive patients treated with ibrutinib for MCL at first relapse. Patients received standard dose 560 mg OD, unless documented, and commenced treatment between August 2014 and April 2019. Response to therapy was defined as per Lugano classification (Cheson et al, 2014), although CR assessment by bone marrow biopsy was not always undertaken. Data was collected on baseline characteristics, including response to prior therapy, and MIPI at time of relapse. The study primary outcome was PFS. Predictors of progression were determined using univariate Cox regression. Results: 169 patients were included in the study. Median age at start of ibrutinib was 72 years (range 33 to 97) and 122 (72.2%) were male. At diagnosis 13.5% had blastoid histology; 59.3% Ki67 ≥30%; 32.0% received cytarabine based induction and 27.8% HSCT consolidation; 11.2% received low intensity frontline therapy (i.e. not fit for R-CHOP) due to frailty. Median PFS following frontline therapy was 21.4 months (95% CI 14.6 to 28.3) and 52.1% progressed within 2 years. At start of ibrutinib 52.2% were MIPI high risk; 23.9% were ECOG 2 or higher and 2.4% had CNS involvement. Overall response rate (ORR) to ibrutinib was 71.6% with 30.4% achieving CR/CRu. Estimated median PFS from start of ibrutinib was 16.5 months (95% CI 11.5 to 21.5) and estimated OS 23.9 months (95% CI 13.0 to 34.8), with median follow up 26 months. Median PFS for patients with early relapse to frontline therapy (progression of disease 1 were also negative predictors of PFS (see table 1 for univariate analysis). 10 patients (5.9%) received attenuated dose from start of therapy due to frailty and 20 patients (11.8%) underwent dose reductions while on therapy due to drug toxicity. Of 109 patients to discontinue ibrutinib 72 (66.1%) were due to progressive disease, 15 for consolidation alloHSCT (13.8%), 13 due to medical co-morbidities and unrelated death (11.9%), and 9 due to drug toxicity (8.3%), including 1 bleed. Only 5.3% of all patients stopped therapy due to drug toxicity. Patients ≥80 yrs were more likely to stop therapy early for reasons other than progressive disease or alloHSCT (OR 2.92, p=0.02), but frailer patients who received low intensity frontline therapy also showed a trend for more durable response with second-line ibrutinib (PFS 10.0 months versus 4.0 months, p=0.36) justifying use in this patient group. Conclusion: This study population is enriched for several recognised adverse prognostic markers, including older age and poor performance status, which is likely to explain differences in PFS relative to clinical trial data. Despite these features response rates were similar, and it is notable that 46.7% of evaluable pts achieved longer PFS with ibrutinib than preceding front-line therapy. It is reassuring that the proportion of patients stopping ibrutinib due to toxicity was similar to trial data and bleeding events that required alterations to therapy were rare (3 cases, 1.8%). Although ibrutinib represents a significant breakthrough with clear benefit to most patients the results also highlight that outcome for many remains poor. 40% of patients progressed within 1 year of starting ibrutinib and median OS post ibrutinib was only 3.6 months. 35.2% of patients died within 1 month of documented relapse suggesting many, predominantly older patients, were not fit for further therapy. Of the 53 pts surviving beyond 1 month median OS was 7.5 months and 21.9% lived beyond 1 year. Improved treatment strategies in the post-ibrutinib setting remains a priority. Disclosures Rule: Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy. Eyre:Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Furtado:Abbvie: Honoraria. Shah:ABBVIE: Consultancy. Campbell:Novartis: Consultancy, Other: Educational support; Takeda: Consultancy, Other: Educational support; Bristol Myers-Squibb: Other: Educational support; Roche: Other: Educational support; Celgene: Other: Educational support. McCarthy:Janssen: Honoraria, Other: Educational grant to attend meetings . Lambert:Takeda Pharmaceuticals: Other: Funding to attend a scientific conference in 2018. McKay:Epizyme: Consultancy, Honoraria. Osborne:Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Gilead: Consultancy; MSD: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Novartis: Other: Travel; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy. Bishton:Takeda: Other: Travel support, Research Funding; AbbVie: Research Funding; Celltrion: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Other: Travel support, Research Funding. Crosbie:Janssen: Honoraria.

The last 20 years has seen considerable advances made in the management of younger patients with mantle cell lymphoma. The use of high dose cytarabine and rituximab in induction therapy, usually followed by autologous stem cell transplant consolidation, has become established practice and the median overall survival now exceeds 10 years. However, this high intensity upfront approach is not necessarily appropriate for all newly diagnosed patients. A minority exhibit disease that behaves in an indolent fashion with no proven benefit from early intervention, and at the opposite end of the spectrum a high-risk group exists who do poorly with conventional treatment. This review considers the role of watch and wait strategies in indolent presentations, examines the evidence behind current induction approaches and considers ways to modify these for those young patients presenting with adverse features. It concludes with an assessment of the emerging role of novel agents and the search for robust risk-adapted treatment strategies.

Patients presenting to primary care often complain about excessive bleeding. The symptom may represent a significant underlying diagnosis that requires urgent specialist referral and treatment, but more often it is less critical in nature and the challenge is to analyse the symptoms and isolate those that warrant further investigation. Here we explore the components of a good clinical history and examination, offer advice on interpreting laboratory tests, and explore case studies of the most important diagnoses.

Background: Mantle cell lymphoma (MCL) is associated with a poor prognosis relative to other indolent B-cell lymphomas where clinicians have traditionally been reluctant to adopt watch-and-wait (W+W) strategies. US registry data from 2004 to 2011 demonstrated 6% of new diagnoses were observed beyond 3 months from diagnosis (Cancer 2016; 122: 2356-63), although other studies have demonstrated higher rates of W+W with no detriment to patient survival. Currently no consensus exists on how to determine suitability for W+W. The MCL Biobank Observational Study was set up to capture clinical behaviour across the United Kingdom and to characterise patients enrolled to W+W compared to those who receive upfront systemic therapy. The study remains open to recruitment. Method: From January 2015 to April 2017 222 patients from 49 centres in the United Kingdom enrolled to the study. All new MCL diagnoses compatible with WHO diagnostic criteria were eligible, with no specific exclusion criteria. Baseline data was recorded at entry including investigator decision to start systemic therapy or enter W+W. Clinical updates were provided at 6 month intervals. In contrast to previous studies W+W was defined as a period lasting at least 1 year from date of diagnosis. Results: All patients were followed-up for a minimum of 1 year. The median age was 70 (range 32-90), 69.4% were male and 47.1% were MIPI high risk. At 1 year follow-up 60 patients (27.0%) were on W+W, 141 (63.5%) received systemic therapy, 16 (7.2%) received isolated radiotherapy and 5 (2.3%) received palliative care. At 2 year follow-up 16 of 85 patients (18.9%) remained on W+W. There were no deaths recorded in patients on W+W. Estimated 2-year survival of the whole population was 80.6%. Univariate analysis comparing baseline characteristics of patients on W+W with those receiving systemic therapy showed no significant difference in age (median age 71.7 vs 69.0; p=0.48), baseline WCC (median 8.0 x 109/L vs 8.9 x 109/L; p=0.09) or performance status (ECOG >1 OR 0.7; p=0.51) meaning the MIPI was not predictive of suitability for W+W (MIPI high risk OR 1.18; p=0.61). Positive predictors for W+W included measures of low disease proliferation: LDH ratio Conclusion: This study demonstrates that adoption of W+W in the United Kingdom significantly exceeds use in previous observational studies and highlights a fundamental shift in clinical approach. The results show that conservative management can be reasonably adopted in a significant proportion of patients. Patients with low disease burden appear best candidates and markers of cell turnover may aid clinical judgement. The MIPI does not have a role in this setting. Longer follow-up will establish if W+W confers survival benefit. Disclosures Pettitt: Celgene: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Gilead: Research Funding; Napp: Research Funding; GSK/Novartis: Research Funding; Chugai: Research Funding. Rule:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees.