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Background Systemic AL amyloidosis is a clonal plasma cell disorder in which amyloid fibrils are deposited in tissues and organs, leading to multi-system organ dysfunction. The most frequently involved organs are the heart and kidney (individually or together), with advanced cardiac involvement conferring particularly poor outcomes. Achievement of hematologic response and improved organ function result in better outcomes. There are currently no approved treatments for AL amyloidosis; multiple myeloma (MM) treatment strategies are used for these pts. Active, tolerable treatment options specific for AL amyloidosis are needed. The oral proteasome inhibitor (PI) ixazomib (ixa) is active and approved in combination with lenalidomide (L)-dexamethasone (Dex) for the treatment of MM pts who have received ≥1 prior therapy. Methods RRAL pts with measurable disease and major organ involvement (cardiac/renal) who required treatment after 1-2 prior therapies (and were not refractory to prior PI therapy) were randomized to ixa (4.0 mg, d 1, 8, 15) plus Dex (20 mg, d 1, 8, 15, 22) or physician's choice (Dex alone or plus melphalan [M], cyclophosphamide [C], thalidomide [T], or lenalidomide [L]) in 28-d cycles until disease progression or unacceptable toxicity (or best response plus 2 cycles or maximum 18 mos therapy/600 mg total dose for MDex). Randomization was stratified by cardiac risk stage, relapsed vs refractory disease, and prior PI exposure. Primary endpoints were 1) overall hematologic response rate (ORR) centrally adjudicated, and 2) death or vital organ deterioration at 2 yrs. Key secondary endpoints were overall survival (OS) and hematologic complete response (CR) rate; other secondary endpoints included hematologic/vital organ progression-free survival (PFS), time to vital organ deterioration or mortality, duration of hematologic response (DOR), and safety. Results 168 pts were randomized to ixa-Dex (n=85) or physician's choice (n=83; 47 LDex, 24 MDex, 10 CDex, 2 TDex); median age was 65 (range 38-84) vs 66 (33-82) yrs, 60% vs 55% were male, 56% vs 63% had cardiac and 66% vs 58% had renal involvement (33% vs 23% had both) at initial diagnosis (plus 9% vs 12% liver, 12% vs 18% gastrointestinal tract, and 11% vs 10% peripheral nerve involvement), 47% vs 47% had prior bortezomib, and 47% vs 37% had prior transplant. Median time since diagnosis was 14.7 vs 15.9 mos. Hematologic responses were seen in 45 (53%) vs 42 (51%) pts receiving ixa-Dex vs physician's choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762). Higher CR rates were seen with ixa-Dex vs physician's choice (26% vs 18%). Overall survival, overall/hematologic/vital organ PFS, time to vital organ deterioration/death, DOR, time to treatment failure, and time to subsequent therapy data all favored pts treated with ixa-Dex vs physician's choice (Figure). Vital organ response rates were 36% in the ixa-Dex arm vs 11% with physician's choice (cardiac response rate: 18% vs 5%; renal response rate: 28% vs 7%). At data cut-off, pts had received a median treatment duration of 11.7 vs 4.9 mos with ixa-Dex vs physician's choice, and 21% vs 6% of pts remained on treatment. Grade ≥3 adverse events (AEs) were seen in 59% vs 56% of pts, including 33% vs 41% with drug-related grade ≥3 AEs, 45% vs 33% had serious AEs, 25% vs 20% had AEs resulting in discontinuation, and there were 6% vs 5% on-study deaths. AEs of clinical importance included diarrhea (34% vs 30%), rash (33% vs 20%), cardiac arrhythmias (25% vs 15%), nausea (24% vs 14%), pneumonia (22% vs 16%), and peripheral neuropathy (20% vs 15%). Common (≥5% overall) grade ≥3 AEs were fatigue (9% vs 9%), anemia (2% vs 10%), cardiac failure, dyspnea (each 6% vs 4%), peripheral edema, and pneumonia (each 5% vs 5%). Conclusions Treatment with ixa-Dex significantly prolonged duration of composite survival and vital organ function, PFS, and time to subsequent therapy vs physician's choice. Moreover, ixa-Dex resulted in an improved CR rate and DOR and, although the primary endpoint of hematologic response was not met, all clinically relevant time-to-event endpoint data favored ixa-Dex vs physician's choice. Ixa-Dex was generally well tolerated and associated with a doubling of treatment duration vs physician's choice; no new safety signals were seen. TOURMALINE-AL1 is the first phase 3 trial in RRAL to show significant outcome improvements, suggesting ixa-Dex represents a new option for RRAL pts, who have limited access to therapies. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Wechalekar:Takeda: Honoraria; GSK: Honoraria; Celgene: Honoraria; Amgen: Research Funding; Janssen-Cilag: Honoraria. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Suzuki:Takeda: Honoraria; BMS: Honoraria, Research Funding; Ono: Research Funding; Celgene: Honoraria; Janssen: Honoraria. Comenzo:Takeda: Research Funding; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Liu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faller:Phoenicia Biosciences: Equity Ownership; Briacell Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Viracta Pharmaceuticals: Equity Ownership; Boston University: Employment. Off Label Disclosure: Investigation of the oral proteasome inhibitor ixazomib in combination with dexamethasone versus physician's choice (of which there are no approved treatment options) for the treatment of relapsed/refractory primary systemic amyloidosis.

Abstract The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

Objectives: In 2014, the Tele-ICU Committee of the Society of Critical Care Medicine published an article regarding the state of ICU telemedicine, one better defined today as tele-critical care. Given the rapid evolution in the field, the authors now provide an updated review. Data Sources and Study Selection: We searched PubMed and OVID for peer-reviewed literature published between 2010 and 2018 related to significant developments in tele-critical care, including its prevalence, function, activity, and technologies. Search terms included electronic ICU, tele-ICU, critical care telemedicine, and ICU telemedicine with appropriate descriptors relevant to each sub-section. Additionally, information from surveys done by the Society of Critical Care Medicine was included given the relevance to the discussion and was referenced accordingly. Data Extraction and Data Synthesis: Tele-critical care continues to evolve in multiple domains, including organizational structure, technologies, expanded-use case scenarios, and novel applications. Insights have been gained in economic impact and human and organizational factors affecting tele-critical care delivery. Legislation and credentialing continue to significantly influence the pace of tele-critical care growth and adoption. Conclusions: Tele-critical care is an established mechanism to leverage critical care expertise to ICUs and beyond, but systematic research comparing different models, approaches, and technologies is still needed.

Abstract Background Schwannomas are rare tumours that pose a significant management challenge in the abdomen, retroperitoneum and pelvis. No data are available to inform management strategy. Methods A collaborative international cohort study, across specialist sarcoma units, was conducted to include adults presenting between 2000 and 2017 with histopathologically confirmed schwannomas within the abdomen, retroperitoneum or pelvis. Results Of 485 patients across 12 centres, 38 (7·8 per cent) were discharged without follow-up, 199 (41·0 per cent) underwent early resection and 248 (51·1 per cent) had radiological monitoring. Of these 248 patients, 96 (38·7 per cent) eventually had surgery, giving an overall resection rate of 60·8 per cent (295 of 485). At baseline, median tumour volume was 90·1 (i.q.r. 26·5–262·0) cm3. The estimated growth rate was 10·5 (95 per cent c.i. 9·4 to 11·6) per cent per year, and was consistent in the short term (within 2 years of diagnosis) and long term (beyond 2 years) (ρ = 0·405, P = 0·021). A decision to operate was more common in symptomatic patients (P < 0·001) and for rapidly growing tumours (growth rate more than 20 per cent per year) (P = 0·025). R0/R1 resection was achieved in 91·6 per cent of patients (263 of 287). Kaplan–Meier long-term recurrence rates after R0/R1 resection were 2·3 and 6·7 per cent at 3 and 5 years respectively. Conclusion Specific recommendations include: indications for early surgery, prediction of growth from radiological monitoring, promotion of selective submacroscopic resection and cessation of postoperative imaging surveillance.

Introduction There have been few recent therapeutic advances in T-acute lymphoblastic leukemia/lymphoma (T-ALL/LBL), a rare and aggressive malignancy. Intensive chemotherapy +/- allogeneic transplantation (AlloHCT) can effect cure, realized by only a minority of adults. In distinction to B-ALL, there have been no safe/effective targeted therapies developed in T-ALL/LBL. We therefore performed a focused tissue array to identify novel tumor proteins, including CCR4; evaluated together with established immunophenotypic (IP) T-ALL/LBL subtypes [early-T-precursor (ETP), early non-ETP (Pre/Pro-T), common & late thymocyte]. We evaluated the clinical phenotype and outcome together with clinical and epidemiologic data in patients diagnosed at the 3-site Mayo Clinic Cancer Center (MCCC: Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Methods Following IRB approval, we identified 50 consecutive T-ALL/LBL patients from 1997 -2019 diagnosed at the 3-site MCCC. Available remnant leukemia/lymphoma paraffin blocks were identified (n=28). Using immunohistochemistry (IHC) we evaluated expression of leukemic antigens of interest (CCR4, CD47, BCL2, BCL6, PD-L1, CD38 and CD123); these were selected based on clinical availability of novel targeted agents, approved or in development for other indications. Tissue array studies were performed and interpreted by a single hematopathologist (L.J) blinded to clinical data, using positive and negative controls, according to standard techniques. We also evaluated the clinical and epidemiological parameters, including different IP subtypes [ETP: CD1a-, sCD3- & CD8-, Pre/Pro-T: CD1a-, sCD3- & CD8+ or CD8- (11 marker T-ALL IP score was used to distinguish CD8- ETP vs. Pre/Pro-T), thymic: CD1a+ and mature: CD1a- & sCD3+] (Khogeer et al., Br J Haematol., 2019) & the presence of the unique MLLT10-PICALM fusion (n=6), as well as therapy and outcome. Comparisons of characteristics and outcomes of interest were made using a Wilcoxon rank sum test (continuous characteristics) or Fisher's exact test (categorical characteristics), unadjusted Cox proportional hazards regression models (overall survival), or unadjusted logistic regression models (complete remission after first line treatment). Results We identified the expression of novel targetable tissue proteins in all adult T-ALL/LBL cases [Table 1]. BCL2, CD38 & CD47 were expressed in majority of the cases, and CCR4 [Fig. 1] was expressed in 11/28 (39.3%) cases. CCR4 expression was significantly more common in the Pre/Pro-T (75%) vs. other IP subtypes (19%) (p=0.011); there was no other association of CCR4 expression with clinical characteristics/outcomes. We also observed differences in T-ALL vs. T-LBL, specifically T-ALL patients were more likely to be male (71% vs. LBL 38.9%, p=0.038). Surprisingly, T-LBL patients were more likely to have a family history of leukemia/lymphoma (41.2% vs. T-ALL 0%, p<0.001). In addition, a significantly different distribution of IP subtype in T-LBL was noted [Table 2]. Not surprisingly, T-LBL patients were more likely to receive 1st line Hyper-CVAD therapy (88.2% v. T-ALL 43.3%, p=0.005), & had a longer delay from diagnosis to initiation of therapy (median 14 vs. 4 days, p=0.012), however this did not appear to impact clinical outcome. In contrast, we observed an important association of IP subtype with outcome after therapy, including complete remission (p=0.035), & a trend suggesting differences in survival (p=0.069) [Table 3]. However, MLLT10-PICALM was not associated with any unique clinical features or with outcome (death, p=0.85; CR, p=0.98), although 4/6 patients underwent AlloHCT, suggesting an important role of AlloHCT in this subgroup. No other significant association of epidemiologic risk factors with phenotype or outcome was noted. Conclusion Using focused tissue array we have identified expression of tumor associated proteins in T-ALL/LBL including CCR4 (Pre/Pro-T IP) & others, which may be targets of therapeutic agents like mogamulizumab. Furthermore, our analysis demonstrates an important clinical impact of IP subtype in T-ALL/LBL, as well as important clinical & therapeutic differences in T-ALL vs. LBL. This study will help guide development of targeted clinical trials in T-ALL/LBL (CCR4 trial already in development). Further analyses are planned to determine the clinical & epidemiologic association of genetic lesions in this cohort. Disclosures Foran: Agios: Honoraria, Research Funding.

Multiple organizations around the world have issued evidence‐based exercise guidance for patients with cancer and cancer survivors. Recently, the American College of Sports Medicine has updated its exercise guidance for cancer prevention as well as for the prevention and treatment of a variety of cancer health‐related outcomes (eg, fatigue, anxiety, depression, function, and quality of life). Despite these guidelines, the majority of people living with and beyond cancer are not regularly physically active. Among the reasons for this is a lack of clarity on the part of those who work in oncology clinical settings of their role in assessing, advising, and referring patients to exercise. The authors propose using the American College of Sports Medicine's Exercise Is Medicine initiative to address this practice gap. The simple proposal is for clinicians to assess, advise, and refer patients to either home‐based or community‐based exercise or for further evaluation and intervention in outpatient rehabilitation. To do this will require care coordination with appropriate professionals as well as change in the behaviors of clinicians, patients, and those who deliver the rehabilitation and exercise programming. Behavior change is one of many challenges to enacting the proposed practice changes. Other implementation challenges include capacity for triage and referral, the need for a program registry, costs and compensation, and workforce development. In conclusion, there is a call to action for key stakeholders to create the infrastructure and cultural adaptations needed so that all people living with and beyond cancer can be as active as is possible for them.

Abstract Introduction Acute graft-versus-host disease (aGVHD) is a significant cause of mortality post allogeneic stem cell transplantation (SCT). First line therapy is corticosteroid based for patients with aGVHD ≥grade (Gd) II. Steroid refractory (SR) aGVHD is associated with a dismal prognosis. Although experimental therapeutics is an unmet need, there is no recent prospective real world data to establish a benchmark for outcomes of best available therapy. We undertook a prospective observational multi-centre international clinical trial of outcomes of second line therapy of steroid refractory aGVHD. The aim was to measure recently defined endpoints including Day 28 (D28) overall response rate (ORR), and 6 month freedom from treatment failure (6mFFTF; defined as a patient (pt) being alive, without relapse of underlying disease or addition of new systemic therapy for aGVHD, prior to the development of chronic(c) GVHD. Methods Data was collected prospectively in a longitudinal observational study in patients starting second line therapy for SR aGVHD. Twelve UK and 2 US sites participated. Adult pts with Gd II-IV aGVHD refractory to corticosteroids were enrolled within 5 days of starting second line therapy. Modified Glucksberg criteria were used to grade aGVHD. Expert panel consensus recommendations (Martin et al 2009) were used for complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) and progressive disease (PD). Kaplan-Meier survival curves and log rank tests for comparison were done on Prism7. Results Between 2014-2018, 64pts were enrolled; 4pts were excluded due to incomplete data. Baseline characteristics of the cohort are outlined in Table 1. GVHD prophylaxis varied according to centre. Forty-seven percent had T depletion; 32% ATG and 25% Alemtuzumab. GVHD was donor lymphocyte infusion (DLI) induced in 7%. At start of second line therapy,5% had Gd I, 27% Gd II and 68% Gd III-IV aGVHD. All patients had received corticosteroids at a minimum dose of 1mg/kg. Second line therapies varied, 60% received ECP and 40% non-ECP therapy including anti-TNF-alpha antibodies (20%), mycophenolate mofetil (MMF) (8%), mesenchymal stem cells (4%) and 'other' (8%). The cumulative incidence of 6mFFTF was 32% (n=19), with 68% (n=41) failing to meet the 6mFFTF endpoint. The causes of failure were, addition of third line therapy in 40% (n=24), relapse 8%(n=5), cGVHD 7% (n=4) and death 13% (n=8). The 6m incidence of death was 45% (n=27); death due to GVHD 30%, infection 8% and relapse 7%. D28 responses were: 56% ORR (8% CR, 28% VGPR, 20% PR), 13% SD, 18% PD and 13% died before D28. Using Kaplan-Meier analysis, median OS was 7.3m with a median follow up of 1 year. The overall cumulative incidence of death was 63% (n=38); GVHD was the leading cause of death 40%, infection 8% and relapse 8%. D28 ORR was associated with a significantly improved median OS not reached versus (vs) 5.2m (p=0.03) in pts who had SD or PD at D28. In pts that achieved 6mFFTF, median survival beyond 6m was not yet reached vs median survival of 3.9m in those that did not achieve 6mFFTF (p=0.0004). The trend was for a longer median OS of 8.2m in the ECP arm vs 5.3m in non ECP (p=0.79). GVHD Gd at start of second line therapy was associated with a longer median survival, not reached in Gd II cohort vs 5.7m in Gd III-IV cohort (p=0.25). Discussion Our multi-centre prospective study illustrates 'real-life' data of clinical outcomes in pts starting second line therapy for SR aGVHD. Median survival from start of second line therapy was 7.3m with a high mortality rate of 63%. D28 ORR was 56% but only 32% met the composite 6mFFTF endpoint, although both outcomes predicted survival. The leading cause for failure of 6mFFTF was starting third line therapy which may be subject to clinician bias, however the 6m mortality was 45%, thus pts went on to die after failing for another cause. This data can be used as a contemporary data while planning studies of experimental intervention vs. best available therapy. Disclosures Radia: Mallinckrodt: Research Funding. Alfred:Mallinckrodt: Speakers Bureau. Dignan:Mallinckrodt: Research Funding, Speakers Bureau. Jagasia:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees.

Abstract BACKGROUND. The detection of minimal residual disease (MRD) at the level of 0.01%/10-4 or above is a strong independent predictor of reduced progression-free (PFS) and overall survival (OS) in patients with CLL treated with chemoimmunotherapy. Although newer agents such as B-cell receptor pathway inhibitors can result in prolonged survival without achieving complete response, there remains a important role for MRD analysis in assessing therapeutic strategies aimed at disease eradication and cure. This is particularly important in front-line trials for fit patients which now require at least five years of follow-up if PFS is used as an endpoint. The feasibility of using MRD as a surrogate or intermediate endpoint for accelerated approval of new treatments is under review by regulatory agencies but further prospective validation is required. At the same time technology is rapidly evolving and high-throughput sequencing (HTS) technologies now detect MRD at the 0.0001%/10-6 level. It is therefore important to determine the most effective approaches for quantifying MRD that are compatible with previous studies but sufficiently sensitive for current treatments. AIMS. This collaborative project had two objectives. First, to identify the simplest and most flexible flow cytometry panel capable of detecting MRD at the 0.01%/10-4 or lower, that is compatible with published data and independent of instrument/reagent manufacturer. Second, to compare the flow cytometry approach with HTS analysis using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). METHODS AND RESULTS. A core panel of antibodies for MRD detection was identified by testing an 8-marker combination in 52 samples (27 post-treatment and 25 dilution study) and re-analysing data with serial exclusion of single markers to determine redundancy. A 1-tube core panel of CD19, CD20, CD5, CD43, CD79b, and CD81 was identified and validated against the previously published 2-tube 6-marker and 4-tube 4-marker ERIC panels in 76 samples (19 post-treatment and 57 dilution study). The results showed good concordance (for log-transformed data above the LoQ, linearity=0.977, Pearson correlation co-efficient=0.983, average difference=0.026 log, 95% limit of agreement 0.20log) and a limit of detection of 0.001%/10-5 for the 1-tube core panel. Inter-operator variation was similar to CML MRD monitoring with both experienced operators, or inexperienced cytometrists after ~1 hour of specific education, achieving a 95% limit of agreement less than 0.3log in samples with MRD levels ranging from 0.0001 – 100%. The flow cytometry approach was compared with the ClonoSEQ HTS assay in 109 samples (21 dilution study and 88 post-treatment samples, complete data currently available on 13/88). The assay was applicable to the vast majority CLL patients, often with two clonal markers. There was 94% concordance at the 0.01% (10-4) threshold (15 samples with ≥0.01% CLL by both methods, 14 samples with <0.01% by both methods, 1 sample with 0.03% CLL by HTS and <0.003% CLL by flow cytometry, and 1 sample with 0.005% CLL by HTS and 0.012% by flow cytometry. HTS detected CLL IGH sequences in 22% (7/31) samples with no detectable CLL cells by flow cytometry (i.e. CLL level 0.0001-0.001%, 3/13 patient samples and 4/18 dilution samples). HTS demonstrated a relatively high variability in quantification, as seen in previous studies, but with a clear superiority in the limit of detection and good linearity (linearity=0.905, Pearson correlation co-efficient=0.870, average difference=0.078 log, 95% limit of agreement 1.5 log). CONCLUSIONS. The 1-tube 6-marker flow cytometry core panel is compatible with published studies, manufacturer-independent and flexible, providing directly quantitative results to 0.001%/10-5 without requiring a pre-treatment sample. HTS requires further work to standardise the quantitative analysis and prospective validation but the ClonoSEQ assay is applicable to >95% of CLL patients, does not require viable cells and is extremely sensitive, detecting residual disease in a significant proportion of cases with <0.01% CLL. The results indicate that flow cytometry and HTS are complementary technologies with a combined approach offering the most reliable way of quantifying CLL at the 0.01%/10-4 threshold while allowing higher sensitivity in clinical trials aimed at disease eradication. Disclosures Rawstron: Roche: Honoraria; Biogen Idec: Consultancy; Gilead: Consultancy, Honoraria; Abbvie: Honoraria; BD Biosciences: Intrasure reagent Patents & Royalties; Celgene: Honoraria; GSK: Honoraria. Williamson:Adaptive Biotechnologies: Employment, Equity Ownership. Sanders:Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Hallek:Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Gilead: Honoraria. Hillmen:Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria, Research Funding.

Abstract BACKGROUND: nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor). Preclinical data show that nal-IRI accumulates in BMs and prolongs survival in animal models of BM. Findings from a phase 1 expansion study (NCT01770353), evaluating patients with mBC and active BM, are reported. METHODS: This phase 1 expansion study enrolled patients with mBC who received multiple prior lines of cytotoxic therapy in the metastatic setting, including one cohort with mBC and active BM, defined as radiographic evidence of new or progressive central nervous system (CNS) metastases after radiation therapy with ≥1 lesion of ≥1 cm in the longest dimension on gadolinium-enhanced magnetic resonance imaging. Patients received nal-IRI 50 mg/m2 (free-base equivalent; FBE) every two weeks (q2w) as an intravenous infusion over 90 minutes, escalating to 70 mg/m2 FBE q2w, if tolerated. RECIST v1.1 and modified RECIST criteria were used to assses non-CNS and CNS disease, respectively. RESULTS: In total, 30 patients were enrolled (10 with active BM). Median age was 53 years (range 29–70 years) and median number of prior cytotoxic anti-cancer regimens was 3 (range 0–6); 29 patients received ≥1 dose of nal-IRI 50 mg/m2 FBE. Overall, nal-IRI monotherapy appeared to be well tolerated, and achieved ≥30% objective response rates for both CNS and non-CNS disease. Among the 10 patients with active BM, 6 achieved CNS disease control (3 partial responses [PRs] and 3 stable disease [SD]), including one patient with durable CNS SD and non-CNS PR for 2 years. Among 7 patients with serial evaluation of CNS metastases posttreatment, 6 patients achieved a reduction in target CNS lesions compared with baseline. CONCLUSION: Treatment with nal-IRI resulted in CNS disease control among 6 of 10 heavily pretreated patients with mBC and active BM. Further exploration of nal-IRI in patients with mBC and active BM is warranted.

Abstract Background nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor), using intraliposomal stabilisation technology to enable high drug load and in-vivo stability. The expansion of Phase I NCT01770353 evaluated nal-IRI in patients (pts) with mBC. Methods This Phase I expansion study enrolled mBC pts (Cohort 1: ER+ and/or PR+ HER2 BC (C-1); Cohort 2: Triple Negative BC (TNBC, C-2); Cohort 3: BC with active Brain Metastasis (C-3)). Key inclusion criteria: ECOG ≤1; adequate organ function; received &gt;1 to ≤5 prior lines of cytotoxic therapy in metastatic setting, except TNBC pts who could have progressed within 12 months of adjuvant therapy. Pts received nal-IRI 50 mg/m2 (Free-base equivalent, FBE) q2w iv infusion, escalating to 70 mg/m2 FBE q2w, if tolerated. Results 30 pts (10 per cohort) were enrolled: 29 received &gt;1 dose nal-IRI 50 mg/m2 FBE (median age 53 yrs, range 29-70 yrs). Median number of cytotoxic therapies prior to study entry was 3. The most frequent treatment emergent adverse events (TEAEs) were gastrointestinal disorders (all cohorts, 100%), primarily diarrhea (C-1, 100% / C-2, 100% / C-3, 70%), nausea (C-1, 80% / C-2, 56% / C-3, 30%), and vomiting (C-1, 60% / C-2, 33% / C-3, 30%). The incidence of neutropenia was low (C-1, 10% / C-2, 0% / C-3, 10%), all grade 1 / 2. Most common grade 3 TEAEs were diarrhea (28%), nausea (17%), fatigue (14%), hypokalemia (10%) and asthenia (10%), with none reported as grade 4. No grade 5 TEAEs were reported. Partial response (per RECIST) was observed in 10 pts for an objective response rate (ORR) of 35% (C-1, 40% / C-2, 33%) / C-3, 30%). Stable disease was observed in 5 pts (17%). Duration of Response (median, months) was C-1, 7.5 (6.4-13.0) / C-2, 5.6 (3.7-7.4) / C-3, 4.1 (0.0-22.2, extracranial: RECIST) / C-3, 1.8 (0.0-1.9, intracranial: mRECIST). Table 1.Study Demographics, Adverse Events, and Best Overall ResponseDemographicsCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=10Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=30Gender, Female, n (%)10 (100%)10 (100%)10 (100%)30 (100%)Age, Years Median (range)56 (49-68)52.5 (37-70)45.5 (29-63)53 (29-70)Race, n (%)WhiteBlack/AfricanOther8 (80%)02 (20%)8 (80%)1 (10%)1 (10%)7 (70%)1 (10%)2 (20%)23(77%)2 (7%)5(16%)Months Since Metastatic diagnosis, Months Median (Range)63.7 (16-87)20.7 (0-34)32.4 (8-55)24.0 (0-87)Number of Prior Cytotoxic Anti-cancer Regimens Median (Range)3.0 (1-6)3.0 (0-5)32.4 (1-6)3.0 (0-6)Safety PopulationCohort 1ER+ and/or PR+ Breast Cancern=10Cohort 2Triple Negative Breast Cancern=9Cohort 3Breast Cancer with Active Brain Metastasisn=10Total PopulationN=29ExposureTreatment Duration, Weeks Median (range)6.1 (0-78)12.3 (0-49)13.9 (1-105)12.3 (0-105)Adverse EventsAny TEAE10 (100%)9 (100%)10 (100%)29 (100%)Grade 38 (80%)6 (67%)10 (100%)20 (69%)Grade 41 (10%)06 (60%)3 (10%)TEAE Related to nal-IRI10 (100%)8 (89%)10 (100%)28 (97%)Grade &gt; 36 (60%)3 (33%)3 (30%)12 (41%)TEAE Related to nal-IRILeading to Dose Adjustment*7 (70%)3 (33%)4 (40%)14 (48%)SAEs6 (60%)4 (44%)7 (70%)17 (59%)SAE Related to nal-IRI4 (40%)1 (11%)1 (10%)6 (21%)Duration of Objective ResponseRECIST 1.1RECIST 1.1RECIST 1.1mRECISTMonths Median (Range)7.5 (6.4-13.0)5.6 (3.7-7.4)4.1 (0.0-22.2)1.84 (0.0-1.9)Best Overall ResponseRECISTRECISTRECISTmRECISTComplete Response (CR)0000Partial Response (PR)4 (40%)3 (33%)3 (30%)3 (30%)Stable Disease (SD)03 (33%)2 (20%)3 (30%)Progressive Disease (PD)5 (50%)2 (22%)3 (30%)2 (20%)Not Evaluable (NE)1 (10%)1 (11%)2 (20%)2 (20%)Objective Response RateCR+PR(95% CI)4 (40%)12.2 -73.83 (33%)7.5-70.73 (30%)6.7-65.33 (30%)(6.7-65.3)*n=1 patient in Cohort 1 discontinued treatment due to TEAE related to treatment with nal-IRI CI, Confidence Interval; nal-IRI, Irinotecan Liposome Injection; SAE, Serious Adverse Event; TEAE, Treatment Emergent Adverse EventSystemic tumor response was evaluated according to RECIST version 1.1CNS tumor response was evaluated according to mRECIST (Anders C. et al., Breast Cancer Res Treat, 2014: 146(3):557-66) Conclusion nal-IRI monotherapy 50g/m2 FBE Q2W appears well tolerated, and achieved &gt;30% ORR for systemic and CNS disease among heavily pre-treated mBC pts regardless of receptor status. Citation Format: Jasgit Sachdev, Pamela Munster, Donald Northfelt, Hyo S. Han, Cynthia MA, Fiona Maxwell, Tiffany Wang, Bruce Belanger, Bin Zhang, Yan Moore, Carey Anders. Phase I expansion study of irinotecan liposome injection (nal-IRI) in patients with metastatic breast cancer (mBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT048.