Abstract: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID . Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure SARS-CoV-2 infection. Main Outcomes and Measures PASC and 44 participant-reported symptoms (with severity thresholds). Results A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%] ) were PASC positive at 6 months. Conclusions and Relevance A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Abstract: Genomic profiling during the diagnosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification, and treatment decisions. Patients for whom diagnostic screening fails to identify disease-defining or risk-stratifying lesions are classified as having B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) of paired tumor-normal samples. For 52 patients with B-other, we compared the WGS findings with data from clinical and research cytogenetics. WGS identified a cancer-associated event in 51 of 52 patients, including an established subtype defining genetic alterations that were previously missed with standard-of-care (SoC) genetics in 5 of them. Of the 47 true B-other ALL, we identified a recurrent driver in 87% (41). A complex karyotype via cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r and IGK::BCL2). For a subset of 31 cases, we integrated the findings from RNA sequencing (RNA-seq) analysis to include fusion gene detection and classification based on gene expression. Compared with RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes; however, RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrated that WGS can identify clinically relevant genetic abnormalities missed with SoC testing as well as identify leukemia driver events in virtually all cases of B-other ALL.

Abstract: 8000 Background: Upfront ASCT for NDTE MM remains under evaluation with high MRD rates following novel induction and consolidation (cons) strategies. Current phase 3 trials support ASCT, however these employ lenalidomide maintenance which predominantly benefits standard risk (SR) patients (pts). The CARDAMON trial investigated the role of ASCT using K based induction and maintenance. Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m 2 biweekly, C 500 mg D 1,8,15, d 40mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons. All received 18 months K maintenance (56mg/m 2 D1,8,15). Flow cytometric MRD (10 -5 ) was assessed post induction, pre-maintenance and at 6 months maintenance. Primary endpoints were ≥VGPR post induction and 2-year PFS from randomisation. 210 randomised pts were needed to exclude a 10% non-inferiority margin with 15% 1-sided alpha, 80% power. Results: 281 pts were registered, median age 59y (33–74), 24% high risk [t(4;14), t(14;16), t(14;20) or del(17p)]. Post induction, ≥VGPR rate was 58.5%, ORR was 87% with similar responses for high risk vs SR. 52 pts did not proceed to PBSCH (6 MR, 16 PD, 19 toxicity, 4 deaths: 3 infection, 1 cardiac event, 7 other). 109 were randomised to ASCT, 109 to KCd cons. ≥VGPR rate was 78.5% after cons and 80.0% after ASCT (p = 0.8). Median KCd cons dose was 55.5 mg/m 2 , 99 (90.8%) pts completed 4 cycles, 104 (95.4%) pts received ASCT. After 2.6 years follow-up, median PFS was not reached for ASCT vs 3.8 years for cons (HR: 0.82 (70% CI 0.65, 1.05, p = 0.4). Observed 2-year PFS for ASCT was 75.5% vs 70.7% for cons; calculated difference in 2-year PFS rate (cons vs ASCT) was -4.5% (70% CI -9.2%, +1.1%, non-inferior). High risk pts had inferior outcomes to SR overall regardless of randomisation (2-year PFS ASCT: 52% vs 82% (HR 4.09); cons 48% vs 77% (HR 2.83)). 2 year PFS did not differ according to randomisation: SR 82% (ASCT) vs 77% (cons) HR: 1.29 (0.71-2.35); high risk: 52% (ASCT) vs 48% (cons) HR: 1.06 (0.50-2.23). MRD negativity post induction was 24.3% and similar by genetic risk. MRD negative rates were higher post ASCT (53.1%) than cons (35.8%) (p = 0.02) independent of genetics: SR 49% (ASCT) vs 36% (cons); high risk: 57% (ASCT) vs 32% (cons). G3+ adverse events to induction were infections (18.7%), hypertension (11.2%), anaemia (10.4%), cardiac disorders (3.6%), vomiting (2.2%), fatigue (2.2%), diarrhoea (1.8%). Conclusions: In NDMM receiving KCd induction and K maintenance, KCd cons was non-inferior to ASCT. High risk pts had inferior outcomes, that were not influenced by ASCT or cons randomisation. Clinical trial information: NCT02315716. [Table: see text]

Abstract: B-other ALL represents a working definition for patients with B cell precursor (BCP) ALL without a known primary chromosomal abnormality. In this study we use whole genome sequencing (WGS) to characterize adult B-other cases (age ≥ 25yrs) from the UKALL14 trial (NCT01085617). Of 652 patients aged 25-65yrs enrolled onto UKALL14, 333 (51%) had B-other ALL. Sufficient material was available to screen 156/333 B-other cases for recurrent Ph-like fusion events (CLRF2, JAK2, ABL1, ABL2PDGFRB) using FISH and MLPA (kit P335). This identified 28 (18%) Ph-like fusion events (21 CRLF2, 5 ABL-class fusions and 2 JAK). Of the remaining 128 B-other cases 57 had available samples for tumor normal paired WGS (read depth 60x and 30x respectively). Bioinformatic analysis was performed to determine small somatic mutations (SSMs); single nucleotide variants (SNVs) and insertion/deletions (INDELs) as well as copy number aberrations (CNA) and structural variants (SV). We also undertook de novo motif analysis to identify RAG mediated deletions. We present data for 30/57 cases (median age of diagnosis 44, range 25-65), the remainder are undergoing sequencing. Within this cohort we identified 784 SVs, 49,244 SNVs and 2,881 INDELs, with each case having a median representation of 23 SVs, 1,674 SNVs and 86 INDELs. The Median SSM burden was 0.55 per megabase (range 0.31-0.81), which is in the upper third of previous ALL estimates (median 0.26 range 0.03-2.9) but low compared to most other cancer types (Alexandrov et al. 2013 Nature). Fusion gene analysis identified 11/30 (37%) cases with recurrent rearrangements (2 ZNF384r, 2 PAX5r, 5 DUX4r and FGFR1r); this identified a novel 5' partner for ZNF384r (AKAP8) and MYO18A-FGFR1 a fusion previously seen in a single case of 8p11 myeloproliferative syndrome. A further 7 clonal coding drivers were identified, 3 PAX5alt, 3 Ph-like candidates and a single ETV6-RUNX1-like candidate (ETV6 R399C, a dominant negative mutation). We classified our cohort into 6 driver subgroups as shown in table 1 using Gu et al. as a framework (Gu et al. 2019 Nat Gen). We found no evidence of driver subgroups clustering with age, although the Ph-like candidates were all identified in patients 39yrs or older. There was evidence that known driver subgroups have differing mutation burdens but these were not significant in this preliminary cohort; the single MEF2Dr case had a high SV burden compared to all other known subgroups (137 vs. cohort median 22); Favorable outcome subgroups (ZNF384r and DUX4r n=7) had a lower SNV coding mutation burden (median 14 vs. 20; U = 60, p = 0.057; Mann-Whitney U test); PAX5alt (n=5) cases had a higher INDEL burden (median 174 vs. 82; U = 16.5, p =0.057). As expected we found recurrent CNA in CDKN2A/B (63%; 19/30), PAX5 (33%; 10/30), IKZF1 (27%; 8/30), ETV6 (11%; 3/30) and BTG1 (7%; 2/30) across the cohort. IKZF1 deletions were enriched in the Ph-like candidate (n=4) subgroup compared to all other known groups (75% vs. 12%; p = 0.028; Fisher's Exact). RAG mediated deletions have been established as an oncogenic driver mechanism in childhood ALL, so we sought to ascertain its role in adults. We identified 54% (128/236) of the breakpoint resolved deletions had a RAG heptamer site. There was a significant difference (U = 167.5, p = 0.021) in RAG deletion burden between patients over 40yrs and under 40yrs at diagnosis (median 1.5 vs 3). Within the unknown driver subgroup; three cases carried ZEB2 H1038R mutations, two with concurrent IGH-CEBPA/B fusions, identifying them as likely belonging to the G12 cluster identified by Li et al. (Li et al. 2018 PNAS); one case had a high translocation burden (37 cohort median 2) and a single case had a high RAG deletion burden (45, cohort median 2); of the remaining 7 cases, four had either a NRAS or FLT3 subclonal hotspot mutation. Here we present the WGS analyses of 30 cases classified as B-other on the basis of no cytogenetic findings by standard clinical assays. The landscape of adult B-other ALL is highly heterogeneous but with WGS we were able to find at least one disease defining event in 60% of our cohort. These events often encompass novel fusion partners of established genomic subtypes or a cytogenetically cryptic lesion such as IGH-DUX4. Taken together our findings demonstrate the clinical utility of WGS as a diagnostic assay to inform and improve the management of adult B-other ALL patients in the future. Disclosures Fielding: Pfizer: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Papaemmanuil:Celgene: Research Funding.

Abstract: Introduction: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) represents a major clinical challenge and is fatal in most patients. Recently Schmitz et al (J ClinOncol 2016), defined an effective risk model, the CNS-IPI, to identify those at highest risk of CNS relapse, based on the international prognostic index (IPI) score and presence of renal or adrenal involvement. For DLBCL patients receiving R-CHOP-like regimens +/- intrathecal methotrexate, the risk of CNS relapse for low, intermediate and high-risk patients was 〈 1%, 3-4% and 10-12%, respectively. The optimum strategy for CNS prophylaxis, however, has yet to be defined. Aim: To assess CNS relapse rates in an intermediate-high risk cohort of patients with DLBCL treated with the R-CODOX-M R-IVAC regimen, incorporating multiple CNS-penetrating agents. Methods: Patients with newly diagnosed DLBCL and an IPI score ≥3 were enrolled in a prospective, multi-centre, phase 2 trial (McMillan et al, Hematol Oncol 2015; 31(S1), 130a) and treated with modified CODOX-M and IVAC, including high dose intravenous methotrexate, cytarabine, ifosfamide and etoposide with 8-12 intrathecal injections (Mead et al, AnnOncol 2002; 23(8):1264-74); plus 8 doses of rituximab. The primary endpoint was progression-free survival (PFS). CNS involvement was diagnosed according to neurological signs, radiological findings and/or demonstration of malignant lymphocytes within the cerebrospinal fluid. Involvement ofextranodal sites was prospectively documented at registration and at relapse. Presence of CNS, adrenal and renal involvement was confirmed using case report forms prior to this post hoc analysis. Results: 108 patients were treated at 32 UK sites between May 2008 and April 2013. Median age was 50 years (18-65 years). Eight patients (7.4%) had CNS involvement at baseline. Eighty-two patients (75.9%) received 4 cycles of treatment. At a median follow-up of 45 months, PFS and overall survival were 65.5% (95% CI: 55.5 - 73.8) and 73.7% (64.0 - 81.2), respectively. Progression or relapse within the CNS occurred in 5 patients (4.6%; Table 1) at a median of 5.5 months after registration (0.9-9.1 months). All patients died within 9 months of CNS relapse, 4 due to DLBCL and one treatment-related death. Excluding those with CNS involvement at baseline or incomplete information (n=4; 2 with missing baseline information (no CNS relapse) and 2 awaiting confirmation of CNS status at relapse), CNS-IPI was evaluable in 96 patients, of which 95% had an elevated LDH, 57% had a performance status of ≥2, and 8% were ≥60 years. All patients had stage III-IV disease, 76% had 〉 1 extranodalsite and 27% had renal or adrenal involvement. Forty-one patients (43%) were intermediate risk (2-3 factors) and 55 (57%) were high risk (4-6 factors) for CNS relapse. 2-year CNS relapse rates were 0% for intermediate risk and 6.2% (2.0 - 18.1) for high risk patients (Figure 1). Of the 3 CNS relapses in high risk patients, 2 occurred concurrently with systemic relapse; there was only one episode of isolated CNS relapse. Of the 8 patients with CNS involvement at baseline, 2 (25%) developed CNS relapse, including 1 isolated CNS relapse. One further patient died of refractory DLBCL whilst 5 (62.5%) are alive and progression free with a minimum of 28 months follow-up. Conclusions: Inclusion of CNS-directed therapy intrinsic to the R-CODOX-M IVAC regimen resulted in very low rates of CNS relapse. Although patient numbers and low event rates make direct comparison difficult, results appear promising alongside historical results with R-CHOP chemotherapy. CNS relapse rates for both intermediate and high risk patients in this trial were below the 95% confidence intervals for CNS relapse reported in large training and validation cohorts by Schmitz et al (0% vs 2.2 - 4.4 and 2.3 - 5.5 for intermediate risk patients and 6.2% vs 6.3 - 14.1 and 7.9 - 16.1 for high risk). Of note, only 2 patients in the whole cohort progressed with isolated CNS disease, one of whom had CNS disease at diagnosis. Thus, where systemic disease was fully treated, treatment failure due to inadequate CNS penetration was rare. Reasonable outcomes were achieved in patients with CNS involvement at diagnosis but greater patient numbers are required to further evaluate this regimen in secondary CNS lymphoma. Table 1 PFS events and CNS relapse rates Table 1. PFS events and CNS relapse rates Figure 1 CNS relapse rates according to CNS-IPI and presence of CNS disease at baseline Figure 1. CNS relapse rates according to CNS-IPI and presence of CNS disease at baseline Disclosures Phillips: Roche: Consultancy. Patmore:Roche: Honoraria; Janssen Cilag: Honoraria. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Montoto:Roche: Honoraria; Gilead: Research Funding.

Abstract: Introduction Earlier studies have indicated that the combination of bortezomib and rituximab is highly active in Waldenstrőm's macroglobulinemia (WM). However, there is scope to improve the complete response rate, duration of response and toxicity profile. We evaluated the efficacy and tolerability of the addition of cyclophosphamide to bortezomib and rituximab in previously untreated patients with WM. Methods Symptomatic treatment-naïve patients were enrolled into this prospective randomised (2:1), multicentre, non-comparative Phase II study (NCT01592981). Patients were stratified according to the International Prognostic Scoring System for WM. Patients were treated with BCR (Bortezomib 1.6 mg/m2 s.c. days 1, 8, 15; Cyclophosphamide 250 mg/m2 oral days 1, 8, 15; Rituximab 375mg/m2 i.v. days 1, 8, 15, 22 cycles 2 and 5 only) or FCR (Fludarabine 40mg/m2 oral days 1-3; Cyclophosphamide 250 mg/m2 oral days 1-3; Rituximab 375mg/m2i.v. days 1, 8, 15, 22 cycles 2 and 5 only) for 6 cycles repeated every 28 days. Rituximab and bortezomib were provided free of charge by Roche and Janssen, respectively. The primary endpoint was investigator assessed overall response rate (ORR) using consensus criteria. Results Sixty patients were enrolled into this study and 59 received trial treatment (BCR=42, FCR=17). Of all registered patients, 73% were male, median (range) age was 67 years (43-87), Haemoglobin 9.8 g/dL (6.5-14.0), serum IgM paraprotein 34 g/L (3.2-80.2), plasma viscosity 3.6 mPa.s (2.0-9.3) and 25/30/45% were low/intermediate/high risk respectively. Six cycles were completed by 92.9% of BCR and 76.5% of FCR patients, one patient withdrew from the study prior to starting trial treatment. Dose reductions were needed in 38.1% of BCR and 52.9% of FCR patients and treatment delays occurred in 64.3% of BCR and 64.7% of FCR patients. ORR was 97.6% in BCR patients with 78.6% achieving a major response (CR=1, VGPR=8, PR=24, MR=7, SD=1), one patient was not assessed as no evidence of WM was found upon central review; 82.4% in FCR patients with a major response rate of 76.5% (CR=0, VGPR=3, PR=10, MR=1, SD=2), one patient stopped treatment after cycle 1 due to continuing cytopenia (grade 4). Responses were also evaluated in both marrow and peripheral blood using a disease specific multiparamater flow cytometric assay. After a median follow-up of 18 months, 54 patients were progression-free; 3 patients progressed (all BCR) and 3 patients died, 2 from myelodysplastic syndrome (MDS) (both FCR) and 1 from pneumonia (BCR). Grade 3 or higher toxicities included anemia (5 [11.9%] BCR; 3 [17.6%] FCR), neutropenia (11 [26.2%] BCR; 12 [70.6%] FCR), thrombocytopenia (7 [16.7%] BCR; 6 [35.3%] FCR) and infection (2 [4.8%] BCR; 5 [29.4%] FCR). No grade 3 or higher neuropathy was reported. Conclusions BCR and FCR are both highly effective treatments for primary therapy of WM but FCR is associated with increased toxicity and concerning incidence of secondary MDS. BCR warrants further investigation in a randomised Phase III trial. Continued follow-up of R2W patients is also important to provide reliable estimates for duration of response, progression-free survival and overall survival. Disclosures Auer: Janssen: Consultancy, Other: Drug provided for clinical trial; Bristol Myers Squibb: Consultancy. Owen:Janssen: Consultancy; Roche: Honoraria; Pharmacyclics: Consultancy.

Abstract: UKALL14 (NCT01085617) randomised 655 patients aged 25-65 years with B-precursor ALL, irrespective of Philadelphia chromosome (Ph) status or cell surface CD20 expression to determine if the addition of four doses of rituximab to standard induction chemotherapy (SOC+R) resulted in improved event free survival (EFS). Patients were recruited between Dec 2010 - Jul 2017 and the primary analysis population comprises 577 patients recruited after an April 2012 amendment in which the SOC therapy was altered. The trial was powered with an 84% chance to detect a 12% improvement in EFS (Hazard ratio (HR): 0.71). Secondary endpoints included complete remission (CR), OS, non-relapse mortality, levels of minimal residual disease (MRD) after induction and relationship of response to CD20 expression. SOC consisted of daunorubicin 30mg/m2, vincristine 1.4mg/m2, dexamethasone 4 day blocks of 10mg/m2 starting d1, 8, 15 and 22. Pegylated asparaginase 1000IU/m2 was added on d4 and 18 (d18 only if & gt;40 years) for Ph- ALL and continuous daily imatinib 600mg for Ph+ ALL. Intrathecal MTX was given on d14. Rituximab 375mg/m2 was given on d3,10,17 and 24. Two patients did not start trial treatment, both were in the SOC+R arm. Analysis is by intention-to-treat. There were 288 patients in the SOC arm and 289 in the SOC+R arm, 273 (95.5%) of whom received all 4 doses of rituximab. The arms were well-balanced for risk characteristics. Of note, 63.9% (SOC) and 62.6% (SOC+R) were aged over 40 years at randomisation and 86 patients in each arm (29.9% and 29.8%, respectively) had Ph+ ALL. CR rate, 92.7% SOC and 94.8% SOC+R, did not differ between the arms. There was no difference in the MRD response between the arms, whether assessed as positive vs. negative or as a continuous variable; 121 (42.2%) of patients were MRD negative at induction completion in the SOC arm vs. 120 (41.8%) in the SOC+R arm. Likewise, the rate of severe/adverse events and non-relapse mortality did not differ between arms. At a median follow-up of 50.5 months (7 days - 83.6 months), 3 year EFS for SOC is 41.9% (95% CI: 35.8 - 48.0) versus SOC+R 48.7% (42.4 - 54.8), Hazard Ratio(HR) 0.88 (0.71 - 1.11), p=0.28, see figure1a. Pre-planned subgroup analyses by cytogenetic ("high risk" was defined as t(9;22), t(4;11), low hypodiploidy/near triploidy and complex karyotype) and other risk groups (age, presenting WBC) as well as by cell surface CD20 expression did not reveal any significant interactions. However, we did find that % blasts expressing CD20 was an independent poor prognostic factor; Youden's cut-off, to determine the best cut-off for a continuous variable, suggested a % CD20 expression of 11.7% as the optimal cut-off. EFS HR for 10-20% CD20 was 1.74 (0.98-3.10) and & gt;20% was 2.20 (1.27 - 3.81), compared to & lt;10% CD20. Outcomes were also analysed by post-induction treatment assignment; myeloablative allogeneic stem cell transplant (MAalloSCT) was assigned for patients with high risk ALL aged 40 and under with suitable donor, reduced intensity-conditioned RICalloSCT was evaluated, as part of the trial, in all patients over 40 years, with suitable donor and consolidation/maintenance was assigned to standard risk/no suitable donor. Of note, there was a large and statistically significant benefit to SOC+R among those who received MAalloSCT, SOC N= 53, 3 year EFS 50.7% (35.9 - 63.7) vs. SOC+R, N=40, 3-year EFS 72.2% (54.9 - 84.2), HR 0.47 (0.23 - 0.95), p=0.03 (figure 1b) which was not evident in the RICalloSCT or maintenance groups and related to a reduction in relapse risk. Among those who received MAalloSCT, SOC and SOC+R, the arms were not totally balanced, with a greater preponderance of high-risk genetics in the SOC+R arm: 29 (64.4%) SOC versus 28 (77.8%) SOC+R, suggesting that the benefit of SOC+R combined with MAalloSCT was able to outweigh some of the adverse genetic risk. By contrast to the GRAALL-2005/R study, in which rituximab was given during all treatment phases, for a total of 16 to 18 infusions, we did not find an overall statistically significant benefit for 4 infusions of rituximab during induction. The non-significant trend to a better outcome with SOC+R underscores the necessity for including 16-18 doses of rituximab to obtain the full benefit. However, our trial shows no treatment interaction of SOC+R with Ph+ status or CD20+ expression level, suggesting that the GRAALL-2005/R results may possibly be generalizable to all patients with B-precursor ALL. Disclosures Rowntree: Novartis: Consultancy. McMillan:Sandoz: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Gilead: Honoraria; Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria; MSD: Honoraria. Menne:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau. Fielding:Amgen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy. OffLabel Disclosure: Rituximab - the agent to which patients were randomised during this study