Abstract: Abstract 4201 Introduction Lenalidomide and dexamethasone is an established treatment for multiple myeloma (MM). We investigated whether changing the dosing schedule reduced treatment costs whilst maintaining efficacy. According to the summary of product characteristics (SPC), the recommended starting dose of lenalidomide is 25mg/day for 21 days every 4 weeks. For grade 3/4 adverse events (AEs), lenalidomide is interrupted until recovery to grade 1 and then dose reduced to 15mg/day. For each subsequent grade 3/4 AE, a further 5mg/day reduction is advised. GCSF is permitted for isolated neutropenia. Within its licensed indication, patients remain on treatment until disease progression (median 10.1 months); however 38% require at least 1 lenalidomide dose reduction due to AEs (Dimopoulos et al. Leukemia 2009). In the UK, the National Institute for Clinical Excellence recommends lenalidomide and dexamethasone at second and subsequent relapse only, with the manufacturer bearing costs after 26 cycles. The incremental cost-effectiveness ratio (ICER) is £43,800 per QALY gained, but at first relapse was deemed too high (more than £69,000 per QALY gained) when compared to bortezomib. The UK price per capsule of lenalidomide (including 20% tax) and the USD equivalent (exchange rate August 2011) is: 25mg £249.60 ($407.56); 15mg £226.80 ($370.25). We therefore investigated the efficacy and costs of alternate day dosing in patients requiring modifications due to grade 3/4 AEs. Methods This was a retrospective review of patients treated with lenalidomide and dexamethasone for relapsed MM in a single UK centre. Treatment commenced with lenalidomide 25mg daily for 21 days per cycle and dexamethasone as per SPC. Upon grade 3/4 AE, lenalidomide was interrupted until recovery to grade 1 toxicity. Dosing was then recommenced at 25mg alternate days instead of 15mg daily. Subsequent dose reductions of 5 mg were made on the alternate day schedule (i.e. down to 15mg, then 10mg, then 5mg on alternate days). The efficacy of this regimen was assessed by IMW response criteria, time to progression (TTP), progression free survival (PFS) and overall survival (OS) according to IMW consensus criteria. Results A total of 42 patients received lenalidomide and dexamethasone of which 39 were evaluable for assessment (2 non-secretory MM, 1 Waldenstroms Macroglobulinaemia). The median age was 68 years (range 37–85) and the median number of prior lines of therapy were 2 (range 1–8). The overall response rate was 85% (PR 59%; VGPR 23%; CR 3%). After a median follow-up of 9.1 months, the median OS was 26.3 months (lower 95% CI of 24.4 months); PFS was 7.7 months (95% CI 4.9–11.6); and TTP was 11.8 months (lower 95% CI of 7.9). The upper 95% values for OS and TTP were not estimated due to few events. The 2 year OS rate was 82.7%. Patients received a median of 6 cycles over 11.7 months with a median duration of response of 7.1 months. These results are comparable to the MM-009/010 phase 3 trials (median TTP 13.4 months; PFS 11.1 months), bearing in mind that our patients were more heavily pre-treated (7% of our patients had 1 prior line compared to 18% in the MM-009/010 trials). 62% of patients required lenalidomide dose modification for AEs (approx. 1.5 times more than MM-009/010). The actual total cost of lenalidomide was £1,450,665.60 ($2,368,901.32) whereas if dose modification according to the SPC was followed, the predicted cost would be £1,914,987.60 ($3,128,254.42). This gives a cost saving of £464,322.00 ($758,615.19) equating to £11,905.69 ($19,455.51) per patient treated. Full cost-effective analysis will be presented at the meeting. Conclusions Whilst lenalidomide and dexamethasone is an effective treatment, dose modifications are required for AEs. Modifying the dosing schedule to alternate days rather than daily dosing at a lower dose resulted in a significant cost saving of £11,905.69 ($19,455.51) per patient treated. Such modifications were more frequent in our dataset due to the heterogeneous characteristics of non-trial patients. Hence this cost-benefit becomes more relevant in those with impaired bone marrow/ renal function and performance status. By making this treatment more affordable this dosing strategy may allow access at an earlier stage in treatment by reducing the ICER per QALY gained. Given the similar efficacy to the conventional dosing scheme, this may represent an alternative and more cost effective way of prescribing. Disclosures: Off Label Use: An alternative method of dosing revlimid.

Abstract: Background. Recent advances in MM therapy create a need for multi-modality response assessments, in order to optimise patient outcomes. Radiological tools can assess the entire skeleton, with the potential to depict heterogeneity of response and help target biopsy of resistant lesions. MRI-based assessment of focal lesions (FL) has been incorporated into the definition of symptomatic MM, providing the rationale for exploring MRI-based response assessment biomarkers. Diffusion weighted imaging derived apparent diffusion coefficient (ADC) has been studied, but standardisation of ADC values across MRI scanners is challenging, limiting generalisability. Fat fraction (FF), also evaluable by MRI, may be a more reliable parameter that could be expected to increase following response to therapy. Methods. This study aimed to evaluate changes in FF in FLs of newly diagnosed MM patients by whole body MRI (WB-MRI) prior to treatment (Pre) and after 8 weeks (8W). WB-MRI was performed on a 3.0 T scanner. Whole-body T2 weighted imaging and axial DWI MRI were supplemented by pre- and post-contrast coronal 2-point mDixon imaging for evaluation of FF. mDixon images were reconstructed as fat only and water only studies. For each patient, up to 20 FLs were localised for analysis by 2 radiologists in consensus, who prospectively scored (score 1-5, 1=highly unlikely, 5=highly likely) involvement of each of 10 anatomical regions. FLs 〉 5mm with score 4 or 5 were selected for quantitative analysis. A matched region of interest (ROI) was contoured for each FL on water only and fat only mDixon images as well as DWI images. FF was derived from ROI signal intensity (SI) by: SIfat/SIwater+SIfat. Estimated tumour volume (eTV) and DWI's ADC of each FL was also calculated. Difference in FF, eTV and ADC between Pre and 8W studies was assessed by Wilcoxon matched pairs test. Disease response was assessed by IMWG criteria. FF, eTV and ADC receiver operating characteristic (ROC) area under the curve (AUC) analysis was conducted for prediction of non-responders at the end of induction. Results. 21 patients (13 male), median age 52 (range 36-69) were enrolled. Patients had IgG (13), IgA (4) or LC MM (4), and 7 had adverse FISH results [t(4;14), t(14;16), 1q+ or del(17p)] with median ISS II (ISS I (8), II (10), III (3)). Each received a bortezomib induction regimen (16 PAD, 3 CVD, 2 VTD) for 4-6 cycles. A total of 325 FLs were analysed in the entire cohort, with a median of 20 (IQR 10-20, mean 15.5) FLs per patient. At baseline (Pre), median or mean eTV, FF or ADC was found to be independent of ISS stage or genetic risk. Fifteen patients (71%) had an overall response (³PR) to induction therapy. Response was not found to correlate with median FL count, baseline (Pre) FF, eTV or ADC. However, at 8W a significant increase in FF was observed in responders (from median 0.25 to 0.47 a.u. at 8W, p 〈 0.0001), but no change was seen in non-responders (p=0.22); eTV significantly decreased in both groups (from median 0.22 to 0.11 and 0.31 to 0.21 for responders and non-responders, respectively p 〈 0.01 and p=0.02). ADC increased in responders (from median 0.79 to 1.46 x 10-3 mm2 /s at 8W, p 〈 0.01) but was not significantly changed in the non-responder group (p=0.2). One responding patient had only 1 FL and was excluded from per patient analysis. Of the remaining 14 responders, 13 had a significant increase in FF (p 〈 0.01-0.02) and decrease in eTV (p 〈 0.01-0.02), the 14th patient had only 4 FLs, with a non-significant increase in FF and no change in eTV; 8/14 demonstrated an increase (p 〈 0.01-0.03) and 1/14 (p=0.01) a decrease in ADC. The remaining patients (5/14) had no significant changes in ADC (p=0.24-0.6). All patients who failed to achieve at least PR (6) had no changes in FF (p values 0.10-0.80); 4/6 had no change in ADC (p=0.10-0.84) whilst 2/6 showed a significant increase (p=0.02, 0.03). All non-responders (6/6) had a significant decrease in eTV (p 〈 0.01-0.02). Percentage changes in FF, eTV and ADC at 8W had an ROC-AUC of 1.0, 0.48 and 0.72 for prediction of response at 6 months. Conclusions. WB-MRI derived FF change of FLs at 8 weeks following induction therapy differentiates responders from non-responders in newly diagnosed MM patients. This may have utility to act as both an early response and predictive imaging biomarker. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Yong: Takeda: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Consultancy; Janssen: Honoraria; Autolous: Consultancy. Popat:Janssen: Honoraria.

Abstract: Background.The overall improvement in treatment outcomes and survival of multiple myeloma (MM) patients has highlighted the persistently poor outlook for patients with del(17p). Around a third of MM patients with del(17p) are also reported to have a TP53 mutation, while this mutation is rare in the absence of del(17p). The prognostic impact of TP53 mutations in the context of del(17p) is unresolved. We investigated the presence of TP53 mutations in a cohort of del(17p) patients to correlate mutation status with clinical outcome. We assessed the types of TP53 mutations, and the timing of mutations in relation to the acquisition of del(17p). Methods. CD138+ plasma cells were obtained from bone marrow of patients at diagnosis and prior to starting each new line of therapy, subjected to FISH analysis using standard probes, and surplus tumour cells banked. Between 2004-2015, we identified 52 patients who had at least one FISH result confirming del(17p) in ≥10% CD138+ cells, of whom 16 patients (30.8%) had del(17p) at diagnosis. In 22 patients, samples were available at more than one time point (2-4) for analysis. Clinical details, including treatment and disease response (2014 IMWG criteria) were collated. Adverse risk FISH was defined as t(4;14), t(14;16) and 1q+. Genomic DNA was extracted from CD138+ plasma cells using DNeasyBlood & Tissue Kit (Qiagen). 87 gDNAsamples were amplified by PCR and screened for TP53 mutations in exons 4-11 using DHPLC. TP53 mutations were verified by Sanger sequencing. Survival was estimated using Kaplan-Meier methods, and differences were assessed by log-rank test with p-values 〈 0.05 considered significant. Results. TP53 mutations were identified in 19 (36.5%) patients, and there was no significant difference in median age at diagnosis between patients with or without mutations (61.3 vs 57.3 years, p=0.07). Of the 16 patients with del(17p) at diagnosis, 5 (31.3%) had a TP53 mutation in the diagnostic sample, while 14 (38.8%) of the 36 patients in the relapse subgroup had a mutation (p=0.8). Of the 18 TP53 variants identified, 17 were single nucleotide variants (SNV), of which 14 (82.4%) were missense mutations, 2 were nonsense mutations and 1 altered a splice site; all were documented on the IARC TP53 database. One patient had a novel in-frame indel. The majority of mutations occurred in exons 5, 6 and 8, which forms an integral part of the p53 DNA binding domain. Most mutations identified were predicted to produce a non-functional protein with less than 20% transcriptional activity, as specified by the IARC database. Eleven (57.9%) of the TP53 mutated patients also had at least one high risk genetic feature compared to 16 (48.5%) of the non-TP53 mutated patients (p=0.6). For relapse patients, median time from diagnosis to acquisition of del(17p) was 34.5 months (range 1-178), and median time from acquisition of del(17p) to TP53 mutation was 4 months ( 〈 1-45). In 3 patients with TP53 mutations detected at relapse, a preceding sample confirmed to harbour del(17p) was non-mutated, and occurrence of the mutation occurred at 24, 37 and 39 months after del(17p) was first detected. A further 2 patients had a sample preceding del(17p) acquisition, in which there was no TP53 mutation. For the remainder of patients, del(17p) and TP53 mutation were picked up simultaneously. Median overall survival (OS) from diagnosis was significantly shorter for TP53 mutated patients (23 vs 74 months, p=0.03). Median OS from time of del(17p) acquisition was also significantly shorter for TP53 mutated patients (14 vs 29 months, p=0.01), although PFS from next line of therapy was similar (7 vs 12 months, p=0.70). The median survival of TP53 mutated patients from first detection of mutant TP53 was 7 months. Summary. TP53 mutations are common in del(17p) MM with a broad range of variants, the majority of which are likely to produce non-functional variant proteins. The acquisition of TP53 mutations seems to occur after allelic loss of 17p, and to confer even worse clinical outcomes. In the era of genomic medicine, there is a case for routinely screening for TP53 mutations in these patients, to aid in management decisions and patient counselling. An urgent need exists to develop therapies to counteract the loss of this tumour suppressor pathway. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Abstract: Background. Survival for older patients with multiple myeloma (MM) has improved with novel agents such as Proteasome inhibitors (PIs) and Immunomodulatory drugs (IMiDs) . Outcomes in this heterogeneous population are also affected by pre-morbid fitness, comorbidities and tolerance of therapy. We analysed the outcomes of first line systemic therapy in this older patient group, aiming to explore the influence of patient, disease and regimen factors on outcomes. Methods. Non-transplant eligible patients undergoing first line therapy between April 2008 and April 2016 were identified retrospectively from electronic prescribing records; patient and disease features, toxicity and dose modifications were obtained from clinical records. FISH was performed on CD138+ cells using standard probes, and adverse risk was defined as per IMWG criteria. Survival was estimated using Kaplan-Meier methods and disease response by IMWG criteria. Cox Regression (univariate and multivariate) analysis was performed to identify factors influencing progression free (PFS) and overall survival (OS). Results. 84 patients were identified with median age 76 years (range 52-97); 24(28.6%) had cardiac and 12(14.3%) had pulmonary comorbidities. There was an equal spread of ISS stage and 26(31.0%) patients had extramedullary disease (EMD). Of 44 patients with FISH results at diagnosis, 18 (40.9%) had high risk features including 9(20.5%) with del(17p). Patients received a range of treatments; 51(60.7%) had PI-based regimens mainly with Bortezomib, 18(21.4%) received IMiDs (13 Thalidomide, 5 Lenalidomide) and 13(15.5%) chemotherapy. The median total duration of therapy including maintenance was 7.7months (range 0.7-24.1); this was longer (9.6months) in patients receiving IMiDs. The median PFS was 13.1 months (95% CI 10.6-15.5) and median OS was 40.5months (95% CI 30.3-50.7). The overall response rate (ORR) was 70.2%, and was higher in patients treated with novel agents (IMiD 72.2%, PI 72.0%) compared to patients treated with chemotherapy (61.6%). Younger age (70-80years vs. ≥80years), ISS stage 1, disease response ≥PR, maintenance therapy and longer total duration of therapy were associated with longer PFS in univariate analysis, and EMD was associated with shorter PFS(p's 〈 0.1). On multivariate analysis, only total duration of therapy (HR=0.89; 0.81-0.96, p=0.005), ISS stage 1 (HR=0.28; 0.12 -0.63, p=0.002) and younger age (70-80years vs. ≥80years HR=0.50; 0.24-1.05, p=0.068) independently predicted longer PFS. Looking at factors predicting OS on univariate analysis, ISS stage 1, IMiD therapy, maintenance therapy and longer duration of therapy were associated with prolonged OS (p's 〈 0.1). Only longer duration of therapy (HR=0.84; 0.76-0.93, p=0.001) and ISS stage 1 (HR=0.25; 0.08-0.80, p=0.020) remained significantly associated with OS on multivariate analysis. Although adverse genetic risk was associated with shorter OS on univariate analysis, the effect was not seen after adjusting for ISS stage, induction regimen and duration of therapy, where only duration of therapy remained significant (HR=0.69; 0.56-0.87, p=0.001). 18 (21.7%) patients discontinued therapy early due to toxicity; this was more frequent with PI (23.5%) and chemotherapy regimens (20.5%) compared to IMiD regimens (16.7%). 48(57%) patients required dose alterations due to toxicity, and this was commoner with IMiD (72%) compared to chemotherapy (38%) or PI (55%) based regimens. Conclusion. We report a sequential cohort of non-transplant eligible patients undergoing first line therapy in the era of novel agents. Our results indicate a consistent benefit for PFS and OS with longer duration of therapy, independent of response, regimen or adverse risk disease. ISS 1 was also an independent predictor of prolonged PFS and OS. Treatment regimen type and response did not correlate independently with PFS or OS. Despite the presence of comorbidities and discontinuations for toxicity, the PFS and OS outcomes are encouraging. This review of real-world outcomes highlights the potential benefit of continuous therapy in older patients. Improved ways of identifying patients susceptible to toxicity and use of frailty-adjusted treatment schedules would further improve outcomes in this patient group. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Abstract: Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10-mg/kg sutimlimab followed by a full dose of 60 mg/kg 1 to 4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase & gt;2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5 g/dL; 95% confidence interval, 2.1-4.5) within 6 weeks (P = .005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3 to 4 weeks after the last dose of sutimlimab. Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. Sutimlimab was safe, well tolerated, and rapidly stopped C1s complement–mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at www.clinicaltrials.gov as #NCT02502903.

Abstract: Introduction Arterial and venous events are known to occur in patients with POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) syndrome which may also include myeloproliferation, with a reported rate in the literature of around 20%. This is higher than in the myeloma cohort where the VTE rate from the UK Myeloma XI study was reported as 11.8%. The approach to optimum management of thrombosis in POEMS patients remains undefined. Method The UCLH POEMS Registry is a comprehensive tertiary centre-based UK data repository including patients from 1999 to the present. Data were collated from patients referred in for diagnosis or after treatment and included blood results, neurological and general performance status, previous and active venous thromboembolism (VTE) and arterial events and their management. Results Of the 103 patients in the UCLH POEMS Registry, 20 were excluded due to missing data. Of the 83 patients included, median age was 52 years (31-84) and 54 (65%) were male. Mean haemoglobin at diagnosis was 143 g/L (89-190), platelet count 443 x10^9 (194-741), vascular endothelial growth factor (VEGF) 3536 pg/mL (388-15422), creatinine 75 μmol/L (32-168) and albumin 40 g/L (31-50). Performance status was ≥ 3 in 15 patients. Radiotherapy was used as a treatment modality in 21/83 (25%) and 48/83 (52%) patients received autografts. There were 51 outpatient-based chemotherapy regimens prescribed. Lenalidomide and dexamethasone (LD) was the most common prescription 30/51 (59%), followed by cyclophosphamide and dexamethasone in 10/51 (20%), LD plus cyclophosphamide in 3/51 (6%), melphalan and steroids 3/51 (6%), cyclophosphamide, dexamethasone and thalidomide 2/51 (4%), LD plus ixazomib 1/51 (2%), velcade, thalidomide and dexamethasone 1/51 (2%) and carfilzomib with dexamethasone 1/51 (2%). Of these 51 outpatient-based chemotherapy scripts, 30 received documented thromboprophylaxis (TP). Prophylactic low molecular weight heparin (pLMWH) was prescribed most frequently (17/30) with 16 of these patients receiving an immunomodulatory based chemotherapy regimen. Other TP agents used include: aspirin (6/30), treatment dose LMWH (tLMWH) (2/30), rivaroxaban (2/30), warfarin (2/30) and clopidogrel (1/30). Twenty-five patients experienced a total of 35 clinically apparent arterial or venous events. Seven had more than 1 thrombotic event, 2 of which developed both arterial and venous thromboses. Three patients had a prior history of VTE;1 with historic DVT developed pulmonary emboli, and 2 had arterial events after historic VTE. Eleven patients had 14 VTEs including DVT (6/14), PE (4/14) and 4 PICC-associated DVT occurring during melphalan-based autograft. Most VTEs occurred during active disease with median VEGF 2731 (444-5000). Five venous events occurred on chemotherapy, including 4 during a melphalan-based autograft, and 1 on LD. VTE occurred despite prophylactic LMWH in 3 patients (2 unknown). Treatment comprised LMWH (4), warfarin (4), or the direct oral anticoagulants, rivaroxaban (1) and apixaban (1). One patient did not receive treatment for a PICC-associated DVT. Sixteen patients experienced 21 arterial events including stroke (7/21), peripheral vascular disease (6/21), MI (4/21) and microvascular disease (2/21). Most events occurred during active disease with median VEGF 3155 (637-10640). Three occurred on anti-POEMS therapy: one patient (VEGF 4555) developed a second stroke on LD and LMWH prophylaxis; one patient on LD (VEGF 10640) and prophylactic rivaroxaban 10mg developed PVD, and another on melphalan and prednisolone (VEGF 2000-4000) and warfarin for atrial fibrillation (target INR 2.0-3.0) developed PVD. Conclusion The venous and arterial event rate in this cohort at 35/83 (42%) is over double that previously reported. There were more arterial events than venous, and most occurred in a state of active disease and off anti-POEMS therapy (26/35), suggesting that treatment-related risk factors are less of a driver for thrombosis than the disease itself. There was no discernible relationship with thrombocytosis. Thromboprophylaxis is commonly used in POEMS patients receiving outpatient-based chemotherapy with the most common agent being prophylactic LMWH. With the high incidence of arterial events in the presence of active disease, the role for anti-platelet agents or indeed DOACs remains undefined in this patient group. Disclosures Thomas: Sanofi: Membership on an entity's Board of Directors or advisory committees. D'Sa:Janssen: Honoraria, Research Funding.

Abstract: Introduction: The optimal management of relapsed/refractory lymphoma is a significant clinical challenge. Early phase clinical trials are primarily designed to assess safety but also represent options for patients with limited therapeutic choices. Outcomes for lymphoma patients on early phase trials have previously been reported as single centre cohorts or grouped analyses with other malignancies. We performed a novel meta-analysis of publically available reports of early phase trials in lymphoma and compared the outcomes with those from our early phase trials unit. Methods: The outcomes of lymphoma patients enrolled on early phase trials at a UK tertiary centre were reviewed. AEs were graded according to CTCAE v4.0 and response criteria evaluated per protocol. Patient and therapy characteristics, AEs and best clinical responses were summarised by descriptive statistics. Individual-patient survival data were analysed using Kaplan-Meier method and survival curves compared with the log-rank test. A systematic literature review was performed using EMBASE, MEDLINE and clinicaltrials.gov to identify publicly available reports of early phase clinical trials reported in 2016-2017 and data was extracted by two independent reviewers. Meta-analyses of ORRs were performed using random-effect models. Results: 50 patients were enrolled onto 9 Phase I and I/II trials between March 2012 and June 2018, Four patients participated in 2 trials, considered separate events. 5 IMPs were small molecular inhibitors, 4 immunotherapies, 4 first in human and 8 investigated as monotherapy. Diagnoses included 42 aggressive NHL (aNHL) [30 DLBCL, 3 PMBCL, 3 Richters, 1 MCL, 5 T cell], 10 indolent NHL (5 WM, 2 FL, 2 MZL, 1 CLL/SLL) and 2 HL. Median age was 54 yr (27-83), 72% male, with a median time from diagnosis of 22.5 months and median 3 prior lines of therapy (range 1-8). Patients received a median number of 2 cycles of IMP (range 1-28) over 57.5 days (IQR: 37-116). 42.6% experienced grade 3-4 toxicity and 31.5% required dose interruptions of 〉 7 days. ORR and clinical benefit rate (≥SD) were 28% and 47% respectively (CR 4%, PR 24%, SD 19%). Patients were followed up for a median of 11.4 months. Median PFS and OS were 2.3 and 6.8 months respectively, with PFS and OS at 3, 6 and 12 months being 45.8%, 34.4%, 26.5% and 58.4%, 45.4% and 38.8%. Median OS was greater for those who received 〈 4 vs ≥ 4 prior lines of treatment (9.6 vs 5.2 months, p-value log-rank test = 0.1) and those with indolent lymphoma vs aNHL (8.2 vs 6.4 months). Patients with DLBCL had a median OS of 6.8 months; ABC subtype had inferior median OS vs GC (3.4 versus 17.6 months [p-value 0.1]). Study withdrawal was due to disease progression, toxicity and allogeneic stem cell transplantation. After trial, 5.6% proceeded to SCT, 33.3% patients received other treatment, 38.9% received palliation (subsequent outcome unknown in 16.7%). 164 lymphoma trial reports were included in the meta-analysis detailing outcomes of 4537 patients (Table 2). All studies were Phase I (72.6%) or I/II and 78% included only patients with lymphoma (all other trials included reported subgroup analysis of lymphoma patients). 95.7% of trials evaluated a single IMP, 52.4% used combinations of agents. IMPs most frequently investigated were small molecule inhibitors (25.6%), antibody-drug conjugates (11.6%) and epigenetic modifiers (10.4%). Immunotherapy trials comprise 36.1% of studies, including ADCs, checkpoint inhibitors (7.32%), naked antibodies (9.2%) and cellular therapies including CAR-T (7.93%). The ORR of all patients was 54.2% (95% CI 49.6% - 58.8%). Subset analysis showed that cellular therapies studies reported a pooled ORR of 62.5% (50.9 - 72.8) and antibody therapies 58.3 (46.7 - 69.2). Conclusion: The outcomes of lymphoma patients on early phase trials is historically perceived as very poor, partly due to the grouping of analysis with other malignancies. Our cohort had an ORR of 28% and OS at 6 months of 58.4%. The meta-analysis of global studies reporting lymphoma specific outcomes, revealed an ORR of 54.2%. This included all histological subtypes and some previously untreated patients. Our cohort was enriched for relapsed aNHL, which may account for the inferior ORR in our cohort. Together, both data sets indicate improved outcomes compared to historical reports and support enrolment of suitable patients into phase I trials when conventional options are exhausted. Disclosures Ardeshna: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Popat:Amgen: Honoraria. Townsend:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria.

Abstract: Background In cold agglutinin mediated autoimmune hemolytic anemia (cAIHA), anti-red blood cell autoantibodies lead to complement-mediated hemolysis with or without symptoms of acrocyanosis after exposure at low temperatures. cAIHA can be divided into cold agglutinin disease (primary CAD) and cold agglutinin syndrome (CAS). The latter is secondary to diseases such as B-cell malignancies including CLL, infections or autoimmune disorders. In primary CAD, more than 90% of patients have a monoclonal IgM (mostly low level) and often a small bone marrow B-cell clone. There is no approved treatment. For patients with significant hemolytic anemia or acrocyanosis despite thermal protection, rituximab is the most accepted first line treatment with an overall response rate of 50% and median duration of response & lt;1 year. Cytotoxic combinations such as rituximab-bendamustine produce more sustained remissions, although with concerns for long-term adverse effects and stem cell toxicity. Studies involving complement inhibitors are showing promising results on hemolysis, although cold induced peripheral symptoms (IgM mediated rather than complement-mediated) will not improve. Recent international guidelines on cAIHA suggest treatment with the Bruton tyrosine kinase (BTK)-inhibitor ibrutinib in refractory patients with cAIHA (Jäger et al Blood Rev 2020). Indeed, the underlying pathophysiology of cAIHA suggest that BTK inhibition could be effective. Aims To evaluate the efficacy of ibrutinib on anemia, hemolysis and acrocyanosis in patients with cold agglutinin-mediated AIHA (CAD/CAS). Methods An international retrospective study was undertaken of cAIHA patients (CAD/CAS) treated with BTK inhibition using a preformed questionnaire. For eligible patients, laboratory and clinical data regarding underlying disease, bone marrow pathology, hemolytic parameters and patient-reported acrocyanosis were collected at diagnosis, 30 days, 3 months, 6 months and 12 months and last date of follow up. Hemoglobin (Hb) response was considered none (NR), partial (PR, & gt;2 g/dL Hb increase or & gt;10g/dL) or complete (CR, & gt;12g/dL). Adverse events were graded according to the Common Terminology Criteria, version-5.0 (2017). Results So far, 10 patients with cAIHA treated with a BTK-inhibitor (all involving ibrutinib) could be included in the study. Patients were followed from April 2014 until June 2020 at 5 centers (Italy (2), Norway, The United Kingdom and The United States). Median duration of follow up was 20 months (1-74 months). The main findings are summarized in table 1. The indication to start treatment was cAIHA based in all but 1 case (CLL). Median previous number of therapies was 2. All patients had a complement-mediated hemolytic anemia, 7 were transfusion-dependent, and 7 reported symptoms of acrocyanosis at the initiation of ibrutinib. After initiation of ibrutinib, all patients showed an improvement in hemoglobin (Median rise: 4.4 g/dL) resulting in 1 PR and 9 CR. All 7 transfusion-dependent patients became transfusion independent (5 within 30 days). In all but 1 patient, markers of hemolysis (LDH, bilirubin) improved after initiation of ibrutinib (see Figure 1). All 7 patients with acrocyanosis reported clear clinical improvement, with complete resolution of symptoms in 5. There was 1 adverse event (grade 1 bleeding). Data collection is still ongoing and future updates are expected. Conclusion Data show that ibrutinib is effective in the treatment of cAIHA with a notable and brisk improvement of both the hemolytic anemia as well as the cold induced peripheral symptoms. Although preliminary, these promising data support further research of BTK-inhibitor based treatment of cAIHA (CAD/CAS) in a prospective study. Disclosures Berentsen: Alexion, Apellis, Bioverativ and Janssen-Cilag: Other: Travel grants ; Alexion, Apellis, Bioverativ, Janssen-Cilag, True North Therapeutics: Honoraria; Apellis, Bioverativ, Momenta Pharmaceuticals and True North Therapeutics: Consultancy; Mundipharma: Research Funding. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Kymera: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon:Bristol-Meyer-Squibb: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. D'Sa:Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. OffLabel Disclosure: BTK-inhibitors (ibrutinib/acalabrutinib) are not yet indicated for the use in (primairy) cold autoimmune hemolytic anemia (cAIHA). However it is indicated for use in Waldenstrom macroglobulinemia (WM) and chronic lymphatic leukemia (CLL). Here we report retrospective data on a cohort of cases treated with ibrutinib for cAIHA mostly secondary to WM or CLL.

Abstract: Background IgM paraprotein-associated peripheral neuropathies (PN) are a heterogenous group of disorders seen in patients with IgM MGUS and Waldenström's Macroglobulinaemia (WM). Anti-myelin associated glycoprotein (MAG) antibodies are causally identified in ~50% of such cases, but other neuropathies with other IgM-targets are described, along with AL amyloidosis and cryoglobulinaemic vasculitis amongst others. Presence of neuropathy alone is typically not an indication for treatment, but progressive disability is. Due to their relative rarity and heterogeneity, the true prevalence and optimal management of these neuropathies is currently unclear. Methods The Rory Morrison WMUK Registry, a national IgM-related disorders database incorporating 18 centres, was searched for all patients with PN and retrospective data clinical data extracted. Research ethics approval was obtained. Results IgM-related PN was identified 153 patients, of whom 99 (64.7%) had underlying WM and 54 (35.3%) had IgM MGUS. Anti-MAG neuropathy was present in 83 (54.6%) patients, anti-ganglioside in 3 (2%), AL amyloid in 7 (4.3%), cryoglobulinemia in 6 (3.7%), one (0.6%) case of CANOMAD syndrome, and a non-MAG IgM-neuropathy in 53 (34.5%%). PN was present at diagnosis in 143 (93.5%) whereas 10 (6.5%) were diagnosed during the course of their disease. Median age at diagnosis was 64 years (30-92) and 101/153 (66%) were male. Table 1 details results at diagnosis. κ-light chain was present in 80.3%, λ in 11.8% and 7.9% had multiple M-protein bands expressing both light chains. MYD88L265P was identified in 44/55 tested patients (80%) and in 23/30 (76.7%) cases of anti-MAG. In those with an IgM-related disorder, 13/20 (65%) had MYD88L265P, higher than in other IgM MGUS patients (7/14, 50%). CXCR4MUT were found in 3/22 (13.6%). Median bone marrow infiltration on trephine was 13% (range 0-85%), but 10 patients had no evidence of disease, 5 had disease on flow cytometry only, 2 an isolated finding of MYD88L265P and 1 isolated CXCR4MUT on PCR. IgM-related PN was seen in 99/719 (13.8%) of all registry patients with WM. At diagnosis, the bone marrow burden, M-protein and B2M were all significantly lower (p & lt;0.001) than in those with WM without PN, despite identical median age. Therapy had been required in 81 (53.3%) patients, including at time of diagnosis in 23 (15%). Median time from diagnosis to treatment was long, at 6.7 years (95% CI 3.2-9.1 years). PN was the sole treatment indication in 64/81 (79%) cases. Time to treatment commencement did not appear to be affected by M-protein quantity or marrow burden, but patients with WM were more likely to have received treatment for their PN (59/108, 54.6%). Frontline treatment incorporated rituximab (R) in 66/81 (81.5%) patients, including R-monotherapy in 30, DRC 20, R-CHOP/R-CVP eight and BR in seven. A major biochemical response was seen in 19/34 (55.9%) patients. Clinical response was seen in 34 of 45 evaluable cases (75.6%), with improvement in 13 (28.9%) and stabilisation in 21 (46.7%). Clinical response or stabilisation was significantly more likely with R-containing therapy (82.1% vs 33.3%, p 0.04), non-amyloid related PN (82% vs 0%, p = 0.01) and attainment of ≥ partial response. All patients (n=12) with normal BMAT or isolated MYD88L265P responded to R-containing frontline therapy, another positive prognostic factor (p = 0.08). Progression of PN occurred after an initiation period of clinical response in 7/34 (20.5%), necessitating re-treatment at a median of 4.3 years after frontline therapy. Median time to 2nd line therapy was 6.7 years, longer than for other WM treatment indications (p = 0.04). Conclusions IgM-related PN is a cause of morbidity for a significant proportion of patients with WM, with a prevalence of 13.7%. However, a third of cases occur in those with IgM MGUS and even very small clonal populations seem capable of causing disease but appear responsive to rituximab therapy. Patients typically have comparatively low systemic disease burden and low rates of CXCR4MUT, perhaps representing a more indolent phenotype or a product of earlier diagnosis. PN is frequently the sole indication for treatment, reflecting this. Clinical improvement or stabilisation was seen in 75% of treated patients, and attainment of ≥50% reduction in IgM (PR) and treatment with rituximab is associated with a more favourable outcome, whereas AL amyloid neuropathy appears to be more treatment resistant. Disclosures Lindsay: Amgen: Other: Travel Expenses; Takeda: Honoraria, Other: Travel Expenses; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Carr:Lupin: Honoraria; CSL: Honoraria; Grifols: Other: Travel support. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pratt:Binding Site Ltd: Other: Personal fees; Amgen: Other: Personal fees; Janssen: Other: Personal fees; Celgene: Other: Personal fees; Takeda: Other: Personal fees; Gilead: Other: Personal fees; Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. D'Sa:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; BeiGene: Honoraria, Research Funding.

Abstract: Background The dose of many anti-cancer medications is calculated based on patient weight or body surface area (BSA). This patient-specific method means that there is almost always leftover drug in the vial which is then discarded. This has been identified as a significant source of wastage and a contributor to the increasing cost of cancer treatment. Bortezomib is a first in class proteasome inhibitor approved for the treatment of multiple myeloma (MM) both at front line and relapse. The starting dose for myeloma is 1.3mg/m2 and the only available preparation in the UK is a vial containing 3.5mg of bortezomib. The list price is GBP 762 ($1,006) per 3.5mg vial. The physical and chemical stability of the reconstituted drug has been demonstrated for 21 days in the original glass vial and in a syringe thereby allowing the preparation of doses in advance of a patient attending for treatment. We carried out a single centre retrospective analysis of the use of bortezomib in patients with MM, with vial sharing to minimise wastage, with focus on practicality and cost saving. Methods Between 27/04/2015 and 15/05/2016 we prepared all scheduled doses of bortezomib in one of two batches each week (changed to a single weekly batch from 11/10/2015) thereby enabling us to share vial contents between patients and minimise drug wastage. Planned bortezomib doses were identified from the hospital electronic prescribing system and ordered from the pharmacy on the Friday of the week prior to treatment. Dispensing occurred under aseptic conditions in the pharmacy sterile production unit using worksheets generated directly from the prescribing system. All doses were prepared for administration by subcutaneous bolus injection as a 2.5mg/ml dilution in sodium chloride 0.9%. The average cost per bortezomib dose was retrospectively calculated by dividing the total acquisition cost of the vials used by the number of doses administered and this was then compared with the cost of using one vial per dose. The cost of wasted doses (those prepared in a batch but not subsequently administered) and doses prepared individually (separately, in addition to the batch) were included to provide a real world assessment of the impact on cost. Results During the 56 week audit period 1489 bortezomib doses were administered to 120 patients, median 26 doses per week (range 19-36), of these, 1331 (89% of total administered) were prepared in one of the vial-sharing batches. The mean actual prescribed dose of bortezomib was 2.36mg (range 1.4-3.0mg). The total number of doses prepared in the batch but not subsequently administered was 75 (5.3%), median 1 per week (range 0-5). Of note, unused doses did not always contribute to drug wastage if an additional vial had not been necessary to accommodate this dose in the batch (27 out of 75 doses). The reasons for unused doses were: individual dose delayed (due to toxicity (n =27), social reason/patient request (n=13), or other reasons (n=7)), bortezomib treatment stopped (due to disease progression (n=12) or toxicity (n=8)) or dose ordered in error for a patient known to have stopped treatment or been delayed (n=8). The total number of doses prepared in addition to the batch was 158, median 3 per week (range 0-6). These doses were for patients who had not been included in the batch due to them not being prescribed in advance (n = 99) or who were missed during the ordering process (n= 59). A total of 1137 vials of bortezomib were used to dispense the doses, of which 979 were used for batched preparation (see table for summary). The median total number of bortezomib vials used each week was 19 (range 15-30) and number of vials saved each week was 7 (range 4-9). Batch preparation and vial-sharing reduced the total cost of bortezomib vials needed from GBP 1,134,618 ($1,497,696) to GBP 866,394 ($1,143,640) representing an overall saving of GBP 268,224 ($354,056). The effective cost of a single bortezomib dose was reduced by 23.6% from GBP 762 ($1,006: the cost of using one vial per dose) to GBP 582 ($768). Batch preparation also reduced dispensing time in the pharmacy and patient waiting times on the day unit as doses were prepared in advance of the day of treatment. Conclusions Sharing the contents of bortezomib vials between patients is logistically feasible and improved patient experience by reducing waiting times on treatment days. Drug costs were reduced by 23.6% resulting in significant savings. This approach should be explored for other suitable drugs. Table Table. Disclosures Cheesman: Janssen: Consultancy. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.