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Risk stratification is essential for the delivery of optimal treatment in childhood acute lymphoblastic leukemia. However, current risk stratification algorithms dichotomize variables and apply risk factors independently, which may incorrectly assume identical associations across biologically heterogeneous subsets and reduce statistical power. Accordingly, we developed and validated a prognostic index (PIUKALL) that integrates multiple risk factors and uses continuous data. We created discovery (n = 2405) and validation (n = 2313) cohorts using data from 4 recent trials (UKALL2003, COALL-03, DCOG-ALL10, and NOPHO-ALL2008). Using the discovery cohort, multivariate Cox regression modeling defined a minimal model including white cell count at diagnosis, pretreatment cytogenetics, and end-of-induction minimal residual disease. Using this model, we defined PIUKALL as a continuous variable that assigns personalized risk scores. PIUKALL correlated with risk of relapse and was validated in an independent cohort. Using PIUKALL to risk stratify patients improved the concordance index for all end points compared with traditional algorithms. We used PIUKALL to define 4 clinically relevant risk groups that had differential relapse rates at 5 years and were similar between the 2 cohorts (discovery: low, 3% [95% confidence interval (CI), 2%-4%]; standard, 8% [95% CI, 6%-10%]; intermediate, 17% [95% CI, 14%-21%]; and high, 48% [95% CI, 36%-60%; validation: low, 4% [95% CI, 3%-6%]; standard, 9% [95% CI, 6%-12%]; intermediate, 17% [95% CI, 14%-21%]; and high, 35% [95% CI, 24%-48%]). Analysis of the area under the curve confirmed the PIUKALL groups were significantly better at predicting outcome than algorithms employed in each trial. PIUKALL provides an accurate method for predicting outcome and more flexible method for defining risk groups in future studies.

Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor–naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), −4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (−76.8% vs −76.0%; difference [95% CI], −0.83% [−5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [−1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], −6.7% [−14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [−8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 96%. For stage I, FFP was 74.1% vs 49.1% for stage II (P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.

Clinical trials in sickle cell disease (SCD) often focus on health care utilization for painful vaso-occlusive crises (VOCs). However, no objective, quantifiable pain biomarkers exist, pain is not specific to VOCs, health care utilization varies between patients, unreported at-home VOCs likely contribute to long-term outcomes, and patient-reported outcomes are seldom considered. This noninterventional, longitudinal, 6-month study aimed to develop tools to identify VOCs in SCD patients with or without health care utilization. Participants wore an actigraph device, tracking sleep and activity. Patients with SCD used an electronic patient-reported outcome (ePRO) tool to collect data on pain, medication, fatigue, and daily function. Patients self-reported when they experienced VOC pain (VOC day). Biomarkers were collected every 3 weeks (non-VOC). Self-reported VOCs triggered at-home or in-hospital blood collection. The study enrolled 37 participants with SCD; 35 completed the study. Participants reported 114 VOC events and 346 VOC days, of which 62.3% and 78.3%, respectively, were self-treated at home. The ePRO and actigraphy captured end points of pain, functionality, fatigue, activity, and sleep; each was significantly altered on VOC days compared with non-VOC days. Biomarkers collected at home or in the hospital on VOC days were significantly altered compared with non-VOC baseline values, including leukocyte-platelet aggregates, microfluidic-based blood cell adhesion, interleukin-6, C-reactive protein, interleukin-10, tumor necrosis factor-α, and thrombin–antithrombin. The Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) trial shows the feasibility of accurately monitoring out-of-hospital pain by using patient-reported VOC days as potential end points for clinical trials in SCD; it describes the changes in biomarkers and activity measured by actigraphy that may enable improved identification and assessment of VOCs.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (

This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.

Spatial intratumor heterogeneity is frequently seen in multiple myeloma (MM) and poses a significant challenge for risk classifiers, which rely on tumor samples from the iliac crest. Because biopsy-based assessment of multiple skeletal sites is difficult, alternative strategies for risk stratification are required. Recently, the size of focal lesions (FLs) was shown to be a surrogate marker for spatial heterogeneity, suggesting that data from medical imaging could be used to improve risk stratification approaches. Here, we investigated the prognostic value of FL size in 404 transplant-eligible, newly diagnosed MM patients. Using diffusion-weighted magnetic resonance imaging with background suppression, we identified the presence of multiple large FLs as a strong prognostic factor. Patients with at least 3 large FLs with a product of the perpendicular diameters >5 cm(2) were associated with poor progression-free survival (PFS) and overall survival (OS; median, 2.3 and 3.6 years, respectively). This pattern, seen in 13.8% of patients, was independent of the Revised International Staging System (RISS), gene expression profiling (GEP)–based risk score, gain(1q), or extramedullary disease (hazard ratio, 2.7 and 2.2 for PFS and OS in multivariate analysis, respectively). The number of FLs lost its negative impact on outcome after adjusting for FL size. In conclusion, the presence of at least 3 large FL is a feature of high risk, which can be used to refine the diagnosis of this type of disease behavior and as an entry criterion for risk-stratified trials.

Introduction Primary myelofibrosis (PM) is a myeloproliferative neoplasm characterised by bone marrow fibrosis and extramedullary hematopoiesis. Both clinical findings and laboratory parameters are used for prognostic scores in Myelofibrosis patients. In addition, the degree of bone marrow fibrosis has an important prognostic value and has correlation with overall survival. Recently, bone marrow fibrosis was correlated with degree of splenic stiffness (SS) measured by imaging elastography techniques. 1,2 Despite these findings, there were patients with insignificant measures that could not be classified according to marrow fibrosis. In order to advance knowledge in this field, we studied splenic and hepatic stiffness (HS) in patients with myelofibrosis using elastography by two methods, ultrasonography (EUS) and magnetic resonance elastography (MRE), and its correlation with prognostic scores and bone marrow fibrosis. Study Design and Methods This is a prospective, cross-sectional, observational study in patients from the outpatient clinic for myeloproliferative neoplasms who had given informed consent according to procedures approved by institution´s ethical committee. Patients with PM, as well as post-essential thrombocythemia (ET) or post-polycythemia vera (PV) myelofibrosis, were included in this study. Myelofibrosis patients with diagnosis of other associated pathologies that may alter SS, as portal hypertension or cirrhosis, were excluded from the study. Patients were assessed for splenic stiffness measured by ultrasound conducted by two examiners, with more than 10 years of experience. EUS was performed in US Epiq 7 equipment - Philips - with ARFI elastometry methodology. The SS measurements was reported in m/s. In addition, they were also evaluated for splenic and liver stiffness by MRI technique. All exams were performed in 1.5 T MR equipment (Magneton Aera, Siemens Healthineers, Erlangen, Germany) and the MRI protocol included T2-weighted and gradient-echo MRE sequences using steady-state 60-Hz excitation and an external driver placed on the right side and, on the left side of the abdomen. The measures of SS were also obtained by two experienced examiners Results At this moment we present the results of 16 patients with myelofibrosis (PM: 8 cases; post-PV myelofibrosis: 2 cases; post-ET myelofibrosis: 6 cases). The median age was 69y (41-88y) and 62,5% of participants were male. The JAK2 V617F mutation was detected in 9 cases; three cases were CALR positive, and three cases were triple negative. The CBC showed: Hb: 10.9 g/dL (6.5-18.7); WBC (x10 9/L): 9.17 (1.8-44.5) and platelets (x10 9/L): 393 (10-957). Our preliminary results show that bone marrow fibrosis increased according to splenic stiffness by EUS and MRE (Figure 1a; table 1). Patients with osteosclerosis also presented a higher SS by MRE (Figure 1b). We could not find correlation of splenic stiffness with prognostic score DIPSS plus, although Int-2/High risk patients presented a trend to be associated with higher liver stiffness. Conclusion To the moment, our preliminary findings suggest a correlation between SS and degree of bone marrow fibrosis and osteosclerosis, though the correlation between both measures and prognostic scores is still to be determined. We expect to have a better definition for all correlations, as we progress through the assessment of the other patients in our service. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction:While the majority of patients (pts) with newly diagnosed classical Hodgkin's lymphoma (cHL) achieve remission following first-line therapy, approximately 30-40% will relapse or become refractory (R/R). Despite R/R status, the 5-year relative survival rate in this population is high (ranging from 78% to 92%) (American Cancer Society 2020). While overall survival (OS) is an unambiguous measure of efficacy in clinical trials, using it as a primary end point requires a long duration of follow-up and may prolong the process of identifying novel and potentially beneficial therapy. Surrogate outcomes, such as progression-free survival (PFS) and time to progression (TTP) are sometimes regarded as valid alternatives when assessing efficacy of a treatment in the absence of mature OS data. The objectives of this study were to assess the conditional survival (CS) given prior PFS among R/R cHL pts treated in the real-world setting. Methods:This retrospective cohort study used electronic medical record (EMR) data of US pts from a network of oncology practices, including practices affiliated with CancerLinQ, maintained in the Definitive Oncology Dataset. Eligible adult (≥18 years) pts who had a confirmed diagnosis of cHL and ≥1 R/R event that occurred between 2000 to 2019 were included. Refractory disease was defined as not achieving a complete or partial response (CR or PR) during a line of therapy. Relapsed disease was defined as the reappearance of cHL at any time after the end of treatment after having achieved a CR or PR. PFS and OS were measured from the start of second-line [2L] therapy to the earlier or disease progression or death; pts without evidence of disease progression or death were censored at the last observed visit. The association between PFS and OS was quantified through the nonparametric Kendall tau rank correlation for bivariate censored data. CS was defined as the Kaplan-Meier probability of surviving an additionalymonths (from the start of 2L), given no OS or PFS event in the previousx(< y) months. Results:A total of 286 R/R cHL pts were included. Most pts were Caucasian (77.3%, n=221) with a median age of 35 years (range: 19-86) at the first R/R event. Median length of follow-up was 12 months from the first R/R event. The most common B symptoms reported were night sweats (38.8%, n=111), weight loss (36.4%, n=104), and fatigue (27.3%, n=78). More than half of pts (54.9%, n=157) received autologous stem-cell transplant (SCT) and 6.6% (n=19) received allogenic SCT. Two-hundred twenty-six pts (79.0%) had documented 2L therapy (first R/R event). From the first R/R event, among these 226 pts, median PFS was 21.0 months (95% confidence interval [CI]: 15.1, 52.5) and median OS was 146.7 months (95% CI: 119.9, not achieved [NA]). CS rates among pts alive without disease progression increased with time: 1-year and 6-year survival rates were 95.7% (95% CI: 91.5, 97.8) and 79.3% (95% CI: 70.5, 85.7), respectively, in pts alive without progression at 3 months, but increased to 100.0% (95% CI: 100, 100) and 94.6% (95% CI: 79.9, 98.6) in pts alive without progression at 3-years (Table). The calculated Kendall tau correlation was 0.42 (p Conclusion:In the real-world setting, R/R cHL pts with longer time without disease progression had lower rates of death and better prognosis. Results from this study support a relationship between PFS and OS; however, further validation and acceptance of PFS as a surrogate endpoint in cHL is required. Establishing these relationships may inform future clinical trial design and interpretation of interim trial data. Disclosures Desai: Merck & Co., Inc:Current Employment, Current equity holder in publicly-traded company.Yang:Merck & Co, Inc.:Current Employment.Gilligan:ConcertAI:Current Employment;Merck & Co., Inc.:Research Funding.Li:Merck & Co., Inc.:Current Employment, Current equity holder in publicly-traded company.Raut:Merck & Co., Inc.:Current Employment.Nahar:Merck Sharp & Dohme, Corp., a subsididary of Merck & Co., Inc., Kenlworth, NJ, USA:Current Employment.

Background. Consensus from prior studies shows that the use of maintenance therapy after completion of combination therapy leads to longer progression-free survival (PFS) for patients with multiple myeloma with some studies showing an overall survival (OS) benefit. Currently, lenalidomide is the standard of care; however, there are limited published data on long-term use regarding ability to sustain minimal residual disease (MRD)-negativity and late toxicities. We were motivated to develop a study focusing on continuous, induction-agnostic lenalidomide maintenance with integration of clinical and correlative data. Here, we report formal results of this phase II study with focus on MRD dynamics and tolerability. Methods. This single arm, phase II trial enrolled 100 evaluable patients. Lenalidomide 10 mg is given days 1-21 on a 28-day cycle. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT at baseline, annually, at progression/end of study; blood work was done every 3 months. The study was statistically powered for the primary endpoint of PFS at 36 months. Correlative assays included MRD testing (10-color single-tube flow cytometry and IGHV sequencing; sensitivity ≤10-5), genomic characterization of detectable disease, and profiling of the bone marrow microenvironment performed on serially banked samples. Results. 100 evaluable patients were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-87 years) and median ECOG score 1 (range 0-1). Prior to enrollment, 22 (30%) patients had high-risk FISH/SNP signature defined as one or more of: 1q+, t(4;14), t(14;16), t(14;20), and 17p- and 48 patients had undergone autologous hematopoietic cell transplantation (AHCT). At abstract submission, median cycles delivered is 39 (range 9-62). 74% of patients have completed ³24 cycles and 55% have completed ³36 cycles. Overall PFS at 36 months was 77% (95% CI: 0.69-0.87) and PFS at 60 months was 63% (95% CI: 0.51-0.78). All patients had MRD testing at least once. 46% were MRD-negative at enrollment. 7 patients who were MRD+ at enrollment converted to MRD-negative. At median follow up 39.4 months (range 7-56 months), 20/100 patients (20%) have progressed. In consideration of the entire follow-up time from initial MRD-negativity, 44 (of 95 tested; 46%) and 37 (of 73 tested; 51%) achieved sustained MRD-negativity at 1 and 2 years, respectively. 22 patients were MRD-negative at 3 years (of 51 tested; 43%). Among those who sustained MRD-negativity for 2 years, with median follow-up of 19 months past the 2-year landmark analysis (max 120 months), there were no progression events. Age, induction regimen, and MRD status at enrollment were the only significant variables associated with PFS regardless of cytogenetic risk or transplant status. At 1 and 2-year landmark analysis, MRD-negativity superseded all else as the most significant factor associated with PFS with HR 0.06(p=0.0004) and HR 1/Inf (p=0.015), respectively. Toxicities (grade 3) included neutrophil count decrease (20%), hypertension (3%), diarrhea (3%), lung infection (2%), and maculo-papular rash (2%), and toxicities (grade 4) include sepsis (2%) and platelet count decrease (7%). The most common non-grade 3/4 toxicities were diarrhea (55%), fatigue (36%), and upper respiratory infection (30%). 7% developed a secondary malignancy on study: 3 adenocarcinoma, 1 squamous cell carcinoma, 1 CMML, 1 MDS, 1 ALL, and 1 glioblastoma. One evaluable patient required dose reduction due to toxicities/tolerability. Conclusions. This prospective study of continuous lenalidomide maintenance, agnostic to induction regimen or AHCT usage, was designed to evaluate the dynamics of MRD-negativity in relation to PFS. It expands on the importance of MRD as a predictor of outcome and illustrates how continuous maintenance therapy can deepen and sustain MRD-negative responses achieved with modern combination therapy. For this cohort, MRD-negativity at each landmark profoundly outweighed the impact of all other variates. Among those who had sustained MRD-negativity at 2 years (37% of the cohort), regardless of MRD status at enrollment, none have had progression events at median 43 months. Our results support cross-sectional MRD testing as a surrogate endpoint for drug approval, and the use of longitudinal MRD tracking in clinical management. Disclosures Korde: Amgen: Research Funding; Astra Zeneca: Other: Advisory Board. Lesokhin:Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; BMS: Consultancy, Honoraria, Research Funding. Smith:Precision Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics: Consultancy. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Mailankody:Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Hultcrantz:Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Hassoun:Takeda: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Scordo:McKinsey & Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Chung:Genentech: Research Funding. Shah:Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Thoren:Sebia: Research Funding; The Binding Site: Research Funding. Ho:Invivoscribe, Inc.: Honoraria. Dogan:AbbVie: Consultancy; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; National Cancer Institute: Research Funding. Giralt:MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; KITE: Consultancy; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; TAKEDA: Research Funding. Landgren:Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Karyopharma: Research Funding; Merck: Other; Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria.

Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) are 2 standards of care for elderly untreated multiple myeloma (MM) patients. We planned to use VMP and Rd for 18 cycles in a sequential or alternating scheme. Patients (233) with untreated MM, >65 years, were randomized to receive 9 cycles of VMP followed by 9 cycles of Rd (sequential scheme; n = 118) vs 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles (alternating scheme; n = 115). VMP consisted of one 6-week cycle of bortezomib using a biweekly schedule, followed by eight 5-week cycles of once-weekly VMP. Rd included nine 4-week cycles of Rd. The primary end points were 18-month progression free survival (PFS) and safety profile of both schemes. The 18-month PFS was 74% and 80% in the sequential and alternating arms, respectively (P = .21). The sequential and alternating groups exhibited similar hematologic and nonhematologic toxicity. Both arms yielded similar complete response rate (42% and 40%), median PFS (32 months vs 34 months, P = .65), and 3-year overall survival (72% vs 74%, P = .63). The benefit of both schemes was remarkable in patients aged 65 to 75 years. In addition, achieving complete and immunophenotypic response was associated with better outcome. The present approach, based on VMP and Rd, is associated with high efficacy and acceptable toxicity profile with no differences between the sequential and alternating regimens. This trial was registered at www.clinicaltrials.gov as #NCT00443235.

Chronic graft-versus-host disease (GVHD) is a pleotropic syndrome that lacks validated methods of measuring response in clinical trials, although several end points have been proposed. To investigate the prognostic significance of these proposed end points, such as the 2005 National Institutes of Health (NIH) response measures, 2014 NIH response measures, clinician-reported response, and patient-reported response, we tested their ability to predict subsequent overall survival (OS), nonrelapse mortality (NRM), and failure-free survival (FFS). Patients (n = 575) were enrolled on a prospective chronic GVHD observational trial. At 6 months, clinician-reported response (P = .004) and 2014 NIH-calculated response (P = .001) correlated with subsequent FFS, and clinician-reported response predicted OS (P = .007). Multivariate models were used to identify changes in organ involvement, laboratory values, and patient-reported outcomes that were associated with long-term outcomes. At 6 months, a change in the 2005 NIH 0 to 3 clinician-reported skin score and 0 to 10 patient-reported itching score predicted subsequent FFS. Change in the Lee skin symptom score and Functional Assessment of Cancer Therapy-Bone Marrow Transplant score predicted subsequent OS. Change in the Lee skin symptom score predicted subsequent NRM. This study provides evidence that clinician-reported response and patient-reported outcomes are predictive of long-term survival. The trial was registered at www.clinicaltrials.gov as #NCT00637689.

Introduction Rituximab maintenance (RM) (375mg/m2 per infusion every 2 months for 3 years) in transplanted patients with mantle-cell lymphomas (MCL) prolongs disease control (LyMa trial, Le Gouill et al NEJM; NCT00921414). However, post-transplant RM might also induce long-term immune deficiency and thus increases risk of infection. To address these issues, we performed an ancillary pre-planned study based on the LyMa trial, a phase III trial that compared RM versus observation (Obs) after ASCT in MCL patients. We compared post-transplant immune-deficiency and its impact on PFS and OS in the RM vs Obs groups. Method All transplanted and randomized patients enrolled in the LyMa trial were eligible for the present study. The following data were collected during the post-ASCT period and monitored according to protocol procedure: febrile event, clinically documented infection, hospitalization for infection, neutropenia, hypogammaglobulinemia and T CD4 lymphocytes count. We also retrospectively collected the use of immune globulin (Ig) substitution. In the LyMa trial, patients were randomized between RM vs Obs after transplantation. To decipher the implication of ASCT or RM in immune recovery, treatment periods were divided in 4: < 6 months after randomization, from 6 to 12 months after randomization, from one to two year after randomization, and from 2 to 3 years after randomization (respectively periods A, B, C and D). Chi-square or Fisher's exact tests were used as appropriate to investigate differences between arms in each treatment period. For all tests, a two-sided p-value Results 240 patients were eligible, 120 in each arm. Patients' characteristics at diagnosis and inclusion were similar in the two arms. Number of hospitalizations due to infections was not statistically different in RM vs Obs in all periods. As previously shown, grade 3/4 infections incidence did not differ in the 2 arms. However, febrile events were more frequent in the RM arm (32 pts vs 11; 38 events vs 12) but this was statistically significant only in C and D periods; p=0,03 for the 2 periods. In all, 51 infections in 44 pts were reported in Obs vs 127 events in 82 pts in RM arm. This difference was also only statistically significant during the C period, p=0,001. Grade 4 neutropenia incidence and T CD4 count did not differ between the two arms in all tested periods. Hypogammaglobulinemia was statistically more frequent in RM during C and D periods (p=0,0001 and p< 0,0001, respectively). Mean level of gammaglobulinemia on D period was 6,50 g/L (range 0,6-11,7) in obs arm versus 4,99 (range 1,0-9,5) in RM arm (p< 0,0001). 36 pts in RM arm vs 10 pts in obs arm were substituted with Ig and the difference was statistically significant only in period D, p Febrile and infectious episodes; neutropenia and T CD 4 lymphopenia did not modify PFS and OS. Patients with gammaglobulinemia < 6g/L in RM arm and in the whole cohort had longer PFS compared to pts who did not present hypogammaglobulinemia : 3-years PFS 93,2% vs 63,5% in RM arm HR = 0,294, 95% CI (0,113-0,767 and), p=0,01 and 3-years PFS 85,6% vs 63,6% in the whole cohort, HR adjusted on treatment arm=0,488 95% CI (0,287-0,830), p=0,008 . PFS was not modified by gammaglobulin level in the Obs arm and it did not modified OS in both arms. We performed a multivariate analysis to determine which data were predictive of infectious events and delayed immune recovery (neutropenia, hypogamma, T CD 4 lymphopenia). This included all univariate parameters with p value < 0,2, among clinical and biological characteristics at diagnosis, response after induction and number of rituximab injections. Interestingly, among others expected parameters, complete response assessed by TDM was predictive of hypogamma with Odd Ratio 2,972 (1,263-6,994) p=0,0126. No value was predictive of neutropenia or T CD4 cytopenia. Conclusion As compared to observation, the use of post-transplant RM does not increase risk of neutropenia and T CD4 lymphopenia. However febrile and infectious events, hypogammaglobulinemia and Ig substitution are more frequent after one year post transplantation. Hypogamma < 6g/L is associated with longer PFS and complete morphologic response. This suggests that hypogammaglobulinemia could be a surrogate for disease response quality and duration. Our findings deserve to be confirmed. Disclosures Thieblemont: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Cellectis: Speakers Bureau; Janssen: Honoraria; University Employement: Current Employment. Bouabdallah:Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Oberic:Roche, Janssen: Other: Travel, Accommodations, Expenses; Roche: Honoraria; Roche, Janssen: Consultancy. Hermine:AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Celgene BMS: Consultancy, Research Funding; Novartis: Research Funding; Alexion: Research Funding; Roche: Consultancy. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria.

Introduction: Isatuximab (ISA) is an anti-CD38 monoclonal antibody that has shown benefit in patients with relapsed/refractory multiple myeloma (RRMM) in combination regimens. This study focuses on the clinical utility and tolerability of ISA based therapies in patients with ISS stage III disease. Methods: Literature search on PubMed, EmCare, Clinicaltrials.gov, Cochrane, and Google Scholar was performed from inception to July 1, 2020, for the use of ISA in MM patients. A total of five clinical trials, including phase Ib/II and phase III trials, were selected for a systematic review out of 109 studies (n=556 patients). Results: The median age was 61-71 years. The addition of ISA to pomalidomide-dexamethasone (PD) in previously treated patients was evaluated by Attal et al. (2019). International Staging System (ISS) stage III disease was present in 28% of the study population at baseline. Patients treated with ISA-PD had a meaningful increase in progression-free survival (PFS) (11.53 versus 6.47 months, P = 0.001, Hazard Ratio (HR): 0.596; 95% confidence interval (CI): 0.436-0.814. PFS benefit was maintained in subgroup analysis based on renal involvement, refractoriness to lenalidomide, and proteasome inhibitors. However, PFS benefit was not statistically significant in ISS stage III disease (HR: 0.64; CI: 0·36-1·11). Martin et al. (2017) evaluated the addition of ISA to lenalidomide and dexamethasone in 57 patients. 22% of the patients had ISS stage III disease. Mikeal et al. also included 9% and 37.1% of patients with ISS stage III MM in their phase Ib and II trials, respectively. All studies demonstrated a significant prolongation of PFS in patients refractory to lenalidomide with ISA administered at 10 mg/kg weekly/every two weeks. Iida et al. (2019) also reported statistically significant improvement in PFS with ISA monotherapy in heavily pretreated Japanese patients (PFS 4.7 months; 95% CI 3.75-NC). In patients with newly diagnosed MM, Ocio et al. (2017) showed encouraging results with an ISA based regimen in 17 patients. ISS stage III disease was present in 88% of the population. At the time of data cut-off, the overall response to treatment was 87%, and 82.4% continued to remain on treatment (see Table 1). Conclusion: ISA as monotherapy and in combination therapy improved surrogate endpoints without increased toxicity in patients refractory to previous lines of treatment. Limited data suggest an improvement in PFS for ISS stage III disease. Long-term results on efficacy in MM with high-risk cytogenetics are awaited. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study (Tefferi et al, Blood Cancer J 2016) supported initiation of a study in TD LR MDS patients. The Phase 2 part of IMerge demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 32%, with median duration of TI being 88 weeks. The responses were seen across different subtypes of LR MDS (Platzbecker et al, EHA 2020, S183). No new safety signal was identified. These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrolment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 130 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of hematologic improvement-erythroid (HI-E), the amount and relative change in RBC transfusions, rate of complete response or partial response, overall survival, progression of MDS, pharmacokinetics, and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Steensma:CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; H3 Biosciences: Research Funding; Astex Pharmaceuticals, Otsuka: Consultancy; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company. Font:Abbvie: Other: Travel, accommodations, expenses; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Jang:Bristol Myers Squibb: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Johnson & Johnson: Honoraria.

Severe Von Willebrand's disease (VWD) may be associated with chronic joint damage and may require prophylactic therapy. In severe VWD, factor VIII (FVIII) levels are low due to rapid clearness. Emicizumab is a humanized bispecific antibody which mimics the function of coagulation factor VIII (FVIII). It has been approved for prophylaxis in hemophilia A. This is the first study assessing the potential role of emicizumab as an alternative prophylactic treatment in a cohort of patients with severe VWD. We present a TG model evaluating patients' hemostasis following ex vivo spiking of their plasma samples with emicizumab. We also report 24 weeks of successful emicizumab prophylaxis in a child with severe VWD and repeated hemarthroses. A cohort of twenty-four VWD patients were included in the study. Fifty-four percent of our patients were males and the cohort consisted of 14 children (≤18 years) and 10 adults. The majority of patients (96%) were of Caucasian origin. Hemarthrosis was encountered in most type 3 VWD patients, whereas none of the type 2 VWD patients had any joint bleeds. Prophylactic treatment was administered in the majority of type 3 VWD patients, whereas type 2 VWD patients largely required only intermittent on demand therapy applied for bleeding episodes or any surgical interventions. Thrombin generation analysis was carried out blindly in plasma obtained from thirteen type 3 VWD patients and eleven type 2 VWD patients. Seventeen healthy volunteers served as a control group. In plasma from type 3 VWD patients, TG was substantially lower than in plasma from type 2 VWD patients, with ETP of 765 nM×min (596-962) vs. 1954 nM×min (1483-2008) (P = 0•001) and peak height of 47 nM (36-65) vs. 262 nM (142-318) (P = 0•002) In order to examine the potential use of emicizumab as an alternative treatment option for type 3 VWD patients, an ex vivo spiking analysis comparing the effect of Haemate P and emicizumab on TG was performed. An improvement in peak height was demonstrated following spiking with both Haemate P concentrations (P = 0•001 for both) and with the higher emicizumab concentration (P = 0•011). Notably, whereas spiking with both Haemate P concentrations increased peak height to near-normal level, spiking with higher emicizumab concentration increased it to a lesser extent (the median was still lower than in normal controls (P = 0•005). Following the decision to treat our impetus patient with emicizumab prophylaxis, TG analyses were performed in the patient's plasma before and during emicizumab loading and maintenance (Figure 3). As expected, patient's initial TG was extremely low and improved following the first administration of emicizumab loading dose (at week 2 after therapy initiation), at which time emicizumab level was 21 µg/mL. Further significant improvement of TG was noted following loading period completion while emicizumab level was 62 µg/mL. Our patient has been treated with emicizumab for more than six months altogether and did not encounter any joint bleeds since the commencement of therapy. During this period, a single dose of Haemate P was administered following tooth exfoliation. Our study contributes towards a better understanding of TG as a surrogate marker of VWD patients' hemostasis. Our data suggests that some severe VWD patients could be safely and efficiently treated with emicizumab. The successful prophylaxis of our patient and our ex vivo laboratory findings should set the ground for further collaborative multicenter studies to examine the efficacy and safety of emicizumab prophylaxis in type 3 VWD patients. Disclosures Barg: roshe: Honoraria, Speakers Bureau. Kenet:PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The use of Emicizumab in sever Von Willebrand disease

β-thalassemia is a hereditary disorder with limited approved treatment options; patients experience anemia and its complications, including iron overload. The study aim was to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This open-label, nonrandomized, uncontrolled study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non–transfusion dependent (mean hemoglobin

Contains fulltext : 202845.pdf (Publisher’s version ) (Open Access) Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

You can only predict things after they have happened. —Eugene Ionesco Is that really true? What is clear is that better surrogate end points are needed for follicular lymphoma (FL) clinical trials so we can predict outcomes before they actually occur; to this end, in this issue of Blood, Cottereau et al provide valuable direction.1 FL is the most common of the indolent non-Hodgkin lymphomas.

A fundamental difficulty in testing “targeted therapies” in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including “organoids” and combinations of pharmacologic and genetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a more open-minded approach to initial eligibility would facilitate quicker identification of responsive subsets. Complete remission without minimal residual disease seems a particularly useful short-term end point. Genotypic and phenotypic studies should be prespecified and performed routinely to distinguish responders from nonresponders.

Monitoring of minimal residual disease (MRD) has become routine clinical practice in frontline treatment of virtually all childhood acute lymphoblastic leukemia (ALL) and in many adult ALL patients. MRD diagnostics has proven to be the strongest prognostic factor, allowing for risk group assignment into different treatment arms, ranging from significant treatment reduction to mild or strong intensification. Also in relapsed ALL patients and patients undergoing stem cell transplantation, MRD diagnostics is guiding treatment decisions. This is also why the efficacy of innovative drugs, such as antibodies and small molecules, are currently being evaluated with MRD diagnostics within clinical trials. In fact, MRD measurements might well be used as a surrogate end point, thereby significantly shortening the follow-up. The MRD techniques need to be sensitive (≤10−4), broadly applicable, accurate, reliable, fast, and affordable. Thus far, flow cytometry and polymerase chain reaction (PCR) analysis of rearranged immunoglobulin and T-cell receptor genes (allele-specific oligonucleotide [ASO]-PCR) are claimed to meet these criteria, but classical flow cytometry does not reach a solid 10−4, whereas classical ASO-PCR is time-consuming and labor intensive. Therefore, 2 high-throughput technologies are being explored, ie, high-throughput sequencing and next-generation (multidimensional) flow cytometry, both evaluating millions of sequences or cells, respectively. Each of them has specific advantages and disadvantages.

Introduction: The use of lenalidomide (LEN) and bortezomib (BTZ) in newly diagnosed multiple myeloma (MM) patients (pts), along with continuous or maintenance therapy paradigm have improved survival outcomes. However, many pts progress while on these agents or discontinue them due to toxicity. There is a need for novel, efficacious, and tolerable regimens that can treat MM pts who are exposed or refractory to LEN or BTZ. The proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab have both been approved as single agents or as components of combination regimens for the treatment of RRMM. The combination of carfilzomib, dexamethasone, and daratumumab has been shown to be efficacious and safe in RRMM in the phase 1 study MMY1001 (Chari, Blood 2019). We present results from the primary analysis of CANDOR, a multicenter, phase 3, randomized study comparing carfilzomib, dexamethasone, and daratumumab (KdD) vs carfilzomib and dexamethasone (Kd) in RRMM pts. Methods: RRMM pts with measurable disease who had received 1-3 prior lines of therapy, with partial response or better to ≥1 line of therapy were eligible. Pts were randomized 2:1 to KdD or Kd. All pts received carfilzomib (K) as a 30-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). Daratumumab (8 mg/kg) was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 wks for 4 cycles (cycles 3 to 6), and every 4 wks thereafter. All pts received 40 mg dexamethasone oral or IV weekly (20 mg for pts >75 years). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), minimal residual disease (MRD) negative-complete response at 12 months (threshold, 10-5 cells), overall survival (OS), time to response, and safety. Results: 466 pts (KdD: 312; Kd: 154) from 102 sites worldwide were randomized. Baseline characteristics were balanced between the two arms. Median age was 64 years. Of the randomized pts, 42.3% and 90.3% received previous LEN- and BTZ-containing regimens, respectively. 33% of pts were LEN-refractory. The primary endpoint of PFS was met after a median follow-up of 16.9 mo and 16.3 mo for the KdD and Kd arms, respectively. Median PFS was not reached for the KdD arm vs 15.8 mo for the Kd arm (HR, 0.63; 95% CI, 0.46-0.85; P=0.0014; Figure). PFS HRs favored KdD vs Kd across prespecified subgroups. Importantly, median PFS (KdD vs Kd) was not reached vs 12.1 mo in the LEN-exposed group (HR, 0.52; 95% CI, 0.34-0.80), and was not reached vs 11.1 mo in the LEN-refractory group (HR, 0.45; 95% CI, 0.28-0.74). Median time to first response was 1 mo in the KdD and Kd arms. ORR was 84.3% vs 74.7% (P=0.0040), and the rate of complete response or better was 28.5% vs 10.4%. MRD-negative complete response rate at 12 mo was 12.5% for KdD vs 1.3% for Kd (P Conclusion: KdD resulted in a significant PFS benefit over Kd, with a 37% reduction in the risk of progression or death. Pts treated with KdD achieved deeper responses, with a nearly 10-times higher MRD negative-complete response rate vs Kd-treated pts. The PFS benefit of KdD was maintained across prespecified clinically important subgroups, particularly among LEN-exposed and LEN-refractory pts. AEs were generally manageable and the incidence of AEs leading to treatment discontinuation was similar in the arms. Overall, KdD was associated with a favorable benefit-risk profile and represents an efficacious new regimen for RRMM, including for LEN-exposed and/or LEN-refractory pts. Figure Disclosures Usmani: AbbVie: Other: Personal fees; SkylineDx: Consultancy, Other: Grant, Personal fees, Research Funding; GSK: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Grant, Personal fees, Research Funding; MundiPharma: Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; Sanofi: Other: Grant, Personal fees, Research Funding, Speakers Bureau; Pharmacyclics: Other: Grant, Research Funding; Merck: Consultancy, Research Funding; Janssen: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Other: Grant, Research Funding; Array Biopharma: Grant, Personal fees, Research Funding; Amgen: Consultancy, Other: Grant, Personal fees, Research Funding, Speakers Bureau. Quach:Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Other: investigator initiated clinical study; Grant, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: investigator initiated clinical study; Grant, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Other: Free drug for investigator-initiated study, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:Glicomimetics: Other: Personal fees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Adaptive: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Landgren:Takeda: Other: Grants, Independent Data Monitoring Committee (IDMC); Rising Tides Foundation: Other: Grants; Amgen: Other: Grant, Personal fees; Seattle Genetics: Other: Grants; NIH: Other: Grants; FDA: Other: Personal fees; Glenmark: Other: Grants; MMRF: Other: Independent Data Monitoring Committee (IDMC); IMF: Other: Grants; LLS: Other: Grants; Perelman Family Foundation: Other: Grants; Karyopharm: Other: Grants; Adaptive: Other: Personal fees; Binding Site: Other: Personal fees; Celgene: Other: Grant, Personal fees; BMS: Other: Personal fees; Cellectis: Other: Personal fees; Juno: Other: Personal fees; Pfizer: Other: Personal fees; Merck: Other: Independent Data Monitoring Committee (IDMC); Janssen: Other: Grants, Personal fees, Independent Data Monitoring Committee (IDMC). Leleu:Sanofi: Honoraria; Takeda: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Amgen: Honoraria; Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; GSK: Honoraria; AbbVie: Honoraria. Siegel:Novartis: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Weisel:Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Juno: Consultancy; GSK: Honoraria. Yang:Amgen: Employment, Equity Ownership. Klippel:Amgen: Employment, Equity Ownership. Zahlten-Kumeli:Amgen: Employment, Equity Ownership. Dimopoulos:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi Oncology: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Genesis Pharma: Research Funding; BMS: Consultancy; Celgene: Consultancy, Honoraria. OffLabel Disclosure: carfilzomib dexamethasone, and daratumumab triplet for relapsed or refractory multiple myeloma

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting 1% of the population, and characterized by deficient or defective von Willebrand factor (VWF). Among women with VWD, up to 80% have heavy menstrual bleeding (HMB), many of whom have depleted iron stores and iron deficiency anemia with reduced physical functioning, anxiety, depression, and poor quality of life. HMB is a serious problem causing significant health burden for those affected. The lack of effective therapies for menorrhagia is a major unmet healthcare need in women with VWD: in up to 30% desmopressin (DDAVP), combined oral contraceptives (COCs) hormones, or the recommended non-hormonal agent, tranexamic acid (Lysteda®, TA) may be ineffective or poorly tolerated. VWF concentrates, including plasma-derived VWF (pdVWF, Humate-P®) and recombinant VWF (rVWF, Vonvendi®) safely reduce bleeds in VWD, but few data exist on VWF use in menorrhagia, and no prospective trials are available to guide treatment. As rVWF has higher purity, potency, and a longer half-life than pdVWF, this phase III trial will compare rVWF with TA in reducing menorrhagia in women with type 1 VWD. Methods: This is an NHLBI-funded U01 phase III multicenter, prospective, randomized, crossover trial in to compare IV rVWF vs. po TA in reducing menorrhagia in type 1 VWD, clinicaltrials.gov, NCT02606045. Women with type 1 VWD, VWF:RCo100 in at least one of the last two cycles, are eligible. Exclusions include hypothyroidism, past thrombosis, and renal disease. Subjects are randomized to rVWF 40 IU/kg IV day 1 vs. TA 1300 mg po three times daily days 1-5 in each of two consecutive cycles. The order of treatment is determined by randomization: in Group 1, rVWF is given in cycles 1 and 2, and TA in cycles 3 and 4; while in Group 2, TA is given in cycles 1 and 2, and rVWF in cycles 3 and 4. A rescue dose day of rVWF 40 IU/kg may be given day 2 of cycles in which rVWF is given. The primary endpoint is a 40-point reduction in PBAC, a validated measure of menstrual loss, after 2 cycles. As rVWF is a greater burden (IV, cost), to show it is superior to TA, it should improve PBAC 40 points more from baseline than TA. Secondary endpoints are cycle severity, cycle length, QoL (SF-36, Ruta, CDC-HRQ0L-14, CES-D), and satisfaction survey. Treatment response will also be compared with VWF assays and VWF genotype. Safety is assessed by number of rescue doses, other bleeding, thrombosis, and allergic reaction. Our research hypothesis is that rVWF will be superior, producing a greater improvement, by at least 40 points, in PBAC, than TA. We also hypothesize that rVWF will be as safe, tolerable, and acceptable as TA, and that VWF assays and VWF genotype will predict response to treatment. A sample size of 60 (inflated to 66 for 5% attrition) will provide 84% power to detect a difference in improvement of 40 points between rVWF and TA. Analysis will be by intent-to-treat analyses, with a two-tailed alternative hypothesis with type 1 error rate of 0.05, a 4-period 2-group (AABB/BBAA) crossover design, and an estimated between-subject standard deviation (SD) of 63 points and within subject SD of 100 points. Results: A total of 442 potential subjects have been identified at 19 participating HTCs, of whom 33 (7.5%) are eligible, and 2 enrolled. The most common reason for ineligibility is use of an IUD (15.6%), COCs (9.4%), age Discussion: In conclusion, rVWF is a high-purity VWF concentrate with a longer half-life than pdVWF. In this multicenter phase III trial, rVWF is being compared to the current non-hormonal standard, TA, to reduce menorrhagia in adult women with type 1 VWD. rVWF is safe and effective in prevention and treatment of bleeds, and this trial will determine if rVWF reduces menorrhagia to a degree sufficient to justify its IV route and cost. Disclosures Ragni: Sangamo: Research Funding; Alnylam/Sanofi: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Biomarin: Consultancy, Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Spark Therapeutics: Consultancy, Research Funding. Seaman:Spark Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Sidonio:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Malec:Hemostasis and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria; CSL: Honoraria. Rodgers:AstraZeneca: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy. Wheeler:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Severe hepatic VOD/SOS is a potentially life-threatening complication of HCT conditioning that may also develop after high-dose chemotherapy. The most severe form of VOD/SOS is often accompanied by multi-organ failure (MOF) and is associated with a mortality rate of >80% when managed with supportive care alone. As part of the marketing authorization in Europe, there was an obligation to set up a disease registry of patients with severe VOD/SOS post-HCT who were treated with defibrotide. The goal of this registry was to collect safety and outcome data and assess patterns of defibrotide utilization in the post-approval setting. This multicenter, multinational, prospective observational study (NCT03032016) was performed by the European Society for Blood and Marrow Transplantation (EBMT). The study included patients with severe VOD/SOS post-HCT who were treated with defibrotide and enrolled from April 2015 to July 2018. Participating centers were members of the EBMT. Physicians registered patients diagnosed with severe VOD/SOS, as assessed by the investigator using classical/standard criteria (including but not limited to hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%), who consented to participate in the study. In addition, patients who were prescribed defibrotide for purposes other than the approved indication (eg, VOD/SOS prophylaxis, treatment of non-severe VOD/SOS or thrombotic microangiopathy) and consented to participate were registered and information collected. There were no specific exclusion criteria; however, treating physicians were alerted to contraindications, special warnings, and precautions detailed in the defibrotide summary of product characteristics. After inclusion, patient information was collected from participating centers at 100 days, 6 months, and 12 months post-HCT. The primary objective was to assess the incidence of specific serious adverse events (SAEs) of interest, which were hemorrhage and site of bleeding, hypotension, coagulopathy, allergic or hypersensitivity reactions, injection-site reaction, infection and septicemia, and thromboembolic events. Secondary endpoints included Day 100 survival, and overall rate of VOD/SOS (and MOF, if present) resolution (based on standard criteria). Summary statistics were calculated for baseline data and safety variables; outcome analyses are descriptive. Here we report an analysis of data with a cutoff of June 18, 2019. Database lock is planned for October 2019, and the presentation will be updated to include the final data. A total of 61 patients with severe VOD/SOS were included; MOF was diagnosed at registration in 34 (56%) patients. The median age of patients with severe VOD/SOS was 14.4 (range: 0-68) years, 34 (56%) aged An SAE of interest occurred in 19 (31%; 95% confidence interval [CI]: 20%-43%) patients with severe VOD/SOS. The most common SAEs of interest by category were infection (n = 13 [21%; 95% CI: 11%-32%]) and bleeding events (n = 8 [13%; 95% CI: 5%-22%]). The most common individual SAEs of interest (≥5% of patients) were pneumonia (8%), gastrointestinal bleeding (8%), and sepsis (5%). Death occurred in 30 (49%) patients within 1 year, with VOD/SOS indicated as a cause of death in 13/30 (43%) patients. The Kaplan-Meier-estimated survival rate at Day 100 for patients diagnosed with severe VOD/SOS post-HCT who were treated with defibrotide was 74% (95% CI: 61%-83%). At latest follow-up, the survival rate was 51%, with median Kaplan-Meier-estimated survival post-HCT not yet reached. VOD/SOS resolved in 46 (75%) patients; the cumulative rate of VOD/SOS resolution at Day 100 was 87% (95% CI: 72%-94%). Resolution of MOF was achieved in 19/34 (56%) patients who had MOF at VOD/SOS diagnosis. In conclusion, among patients with severe VOD/SOS post-HCT (with/without MOF), the incidence of SAEs of interest was consistent with that observed in previous defibrotide clinical trials. Treatment with defibrotide resulted in high rates of Day 100 survival and VOD/SOS resolution. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Blaise:Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Pierre Fabre medicaments: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Hanvesakul:Jazz Pharmaceuticals: Employment, Equity Ownership. Ryan:Jazz Pharmaceuticals: Employment, Equity Ownership. Lawson:Jazz Pharmaceuticals: Consultancy, Honoraria.

Introduction: Whether sickle cell disease (SCD) or its primary treatment, hydroxyurea (HU), limits reproductive potential in affected women is unknown. Females are born with a finite number of eggs. Anti-Mullerian Hormone (AMH), produced by immature ovarian follicles, is an established method to measure ovarian reserve. Two studies of AMH, one in adolescents with SCD and another in adult women with SCD exist, but neither normal AMH values nor the effect of HU on AMH are established in girls and women with SCD. The purpose of this study is to evaluate AMH levels in women who participated in the seminal study that led to FDA-approval for HU in adults with SCD, the Multi-Center Study of Hydroxyurea (MSH). Methods: The MSH was a randomized placebo-controlled trial (RCT) of HU. The RCT demonstrated HU's efficacy, so a 10-year MSH extension study was conducted to assess HU's potential for "mutagenesis, teratogenesis and oncogenesis". Although no samples from the RCT remain, serum samples (n=285) were available for many women in the follow-up study (n=93). We measured AMH in these samples using the CLIA-certified electrochemiluminescence assay in clinical use at our institution (Esoterix Labs, Calabasas Hills, CA). The assay's reference median AMH in women ages 26 - 30 years is 4.20 ng/mL, and in women 36 - 40 years is 1.69 ng/mL. The assay's lower limit of detection is 0.015ng/mL. Samples with AMH levels beneath the detection limit were run in duplicate when sufficient sample existed; this did not change any results. Here, we report AMH levels in female subjects (n=57) with a serum sample from the first annual follow-up visit (AV01). Descriptive statistics with median values reported for non-parametric variables (Mann Whitney U Test) were performed. AMH < 1 is associated with diminished ovarian reserve, a risk factor for shortened reproductive lifespan, infertility and poor outcomes with assisted reproductive technology. Therefore, we categorized AMH as normal (>/= 1 ng/ml) and low ( Results: Samples from the first post-study visit were available for 57 women; the median time to first post-study visit was 31 months (IQR 6.5) after RCT closure. Median values for the cohort were: AMH, 0.306ng/ml (IQR 1.162), age, 32.50 years (IQR 11), MCV, 102.0 fl (IQR 15.8), and HU exposure, 23.92 months (IQR 30.72). Figure 1 shows AMH distribution in the cohort. AMH levels were low in 77% (44 of 57) of the cohort. Table 1 compares patient characteristics of subjects with low AMH (n=44) versus normal AMH (n=13). In univariate analysis, subjects with low AMH were older (34.5 vs 24.5, p Conclusions: Most women (77%) in this cohort had low AMH, associated with older age and higher MCV. This preliminary analysis raises concerns about diminished ovarian reserve in women with SCD. Although months of HU exposure was not associated with low AMH, HU exposure does not account for adherence, which is a major limitation in most sickle cell studies. MCV which increases with consistent HU use and is a biological proxy measure of the last 3-months of HU adherence, was associated with low AMH. Ovarian reserve was not a planned endpoint in the MSH. A prospective study of ovarian reserve in women with SCD is needed to understand how the physiology of SCD itself or exposure to HU may influence multiple fertility endpoints. Disclosures Chaturvedi: Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Lanzkron:PCORI: Research Funding; NIH: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding.

Background: Portal vein thrombosis (PVT) is a common complication of liver cirrhosis but can also be seen in non-cirrhotic patients. In this context, we present a single institution experience of PVT in our patient population contrasting the difference of presentation between both groups of PVT. Methods: We retrospectively analyzed electronic medical records of patients with PVT (confirmed with radiographic criteria) from 2009 to 2018. We collected data regarding the demographics, characteristics of PVT, liver cirrhosis, presence of malignancy, treatment and laboratory investigations done at the time of diagnosis. Clinical endpoints of 90-death mortality, admission to intensive care unit and length of stay were also collected. Results: a total of 162 patients fulfilled inclusion criteria. 104 (64.2%) male patients, mean age of 56.4, predominantly African American patients 75 (46.3%). 81 (50.0%) patients had cirrhotic PVT and 85 (52.5%) had malignant PVT. Most patients presented with abdominal pain 102 (63%), with an acute onset 51 (31.5%). 111 (68.5%) patients were not treated with anticoagulation. 28 (17.3%) patients died within 90 days of diagnosis and 22 (13.6%) patients were admitted to intensive care unit during same admission. When comparing Malignant with non-malignant PVT, patients with malignancy had a higher death rate 22 (30.1%) vs 6 (8.8%), p value Conclusion: In terms of etiology, PVT patients with malignancy seem to be doing worse than patients without malignancy while patients with cirrhosis except for higher rates for MICU admission; they seem to be doing similarly. Reasons for this discrepancy could be attributed to the fact that malignancies associated with high rates of PVT seem to be more aggressive in terms of mortality. Other studies need to be conducted in order to further clarify what we know about malignant and cirrhotic PVT. Table Disclosures No relevant conflicts of interest to declare.

Background: Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin (Hb) polymerization and red blood cell sickling, leading to chronic anemia and hemolysis as well as episodic vaso-occlusive crises (VOC). These manifestations of SCD contribute to the cumulative organ damage that leads to disability, reduced quality of life, and accelerated mortality. In particular, VOCs and their associated episodic pain are a hallmark symptom of SCD and frequently require emergency medical attention. Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor in development for the treatment of SCD. It has demonstrated robust, rapid, and sustained improvements in patient Hb levels with numerically fewer VOCs compared with placebo, which suggests that viscosity was not increased with voxelotor treatment. The objective of this study was to further explore this observation by examining the association between absolute Hb achieved by voxelotor treatment and VOC incidence rate. In addition, to inform on the potential for symptom exacerbation after drug discontinuation, rates of VOCs after voxelotor discontinuation were analyzed. Methods: The HOPE trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo for ≥24 weeks in patients with SCD aged 12 to 65 years. The primary endpoint is the percentage of patients with a Hb response at week 24, defined as a >1.0 g/dL increase in Hb. Secondary endpoints included the annualized incidence rate of VOC. This abstract reports a post hoc analysis of VOC incidence in the per-protocol population stratified by Hb level at 24 weeks of treatment. In addition, VOCs in patients who discontinued voxelotor and completed a 28-day follow-up are reported here (data cutoff October 31, 2018). Results: The proportion of patients with ≥1 VOC was 67.0% (59/88) in the voxelotor 1500 mg group, 66.3% (61/92) in the voxelotor 900 mg group, and 69.2% (63/91) in the placebo group. Overall, the annualized adjusted incidence rate of VOCs (the number of crises per person-year) was 2.77 in the voxelotor 1500 mg group, 2.76 in the voxelotor 900 mg group, and 3.19 in the placebo group. When stratified by Hb level after 24 weeks of treatment, the incidence of VOCs was generally lower in patients who achieved higher absolute Hb levels on voxelotor treatment compared with placebo (Figure 1). Patients who discontinued voxelotor were also observed for 28 days post-treatment. At the time of data cutoff, 55 patients (n=21, voxelotor 1500 mg; n=17, voxelotor 900 mg; n=17, placebo) had discontinued treatment and had post-treatment follow-up. During the 28-day period after treatment discontinuation, 5 patients in the voxelotor 1500 mg group reported 6 VOCs; 3 patients in the voxelotor 900 mg group reported 3 VOCs; and 5 patients in the placebo group reported 8 VOCs. The estimated incidence rates of post-treatment VOCs were 4.63, 4.30, and 7.01 in the voxelotor 1500 mg, voxelotor 900 mg, and placebo groups, respectively. Conclusions: Patients who achieved the greatest absolute Hb level after 24 weeks of treatment with voxelotor had numerically fewer VOCs, suggesting that increasing Hb levels resulting from voxelotor treatment did not lead to a viscosity-related increase in risk of vaso-occlusion. Following drug discontinuation, there was a numerically lower incidence of VOCs in the voxelotor arms compared with placebo. Altogether, these results suggest that voxelotor treatment safely raises Hb without causing a viscosity-related increased risk of VOC and that treatment discontinuation did not increase risk for VOC. Disclosures Vichinsky: GBT: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Telfer:ApoPharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker activities, clinical trial activities; Terumo: Honoraria, Other: Speaker activity; Pfizer: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: clinical trial activity; Kyowa Kirin Limited: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial activities; Napp Pharma: Other: clinical trial involvement; Celgene: Other: clinical trial involvement; Bluebird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Inati:Global Blood Therapeutics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Ataga:Modus Therapeutics: Honoraria; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Solitary plasmacytoma (SPC) is a rare plasma cells disorder, which may present as a single bone lesion or an extramedullary plasmacytoma. High dose radiotherapy may be curative, yet most patients eventually develop Multiple Myeloma (MM). Due to rarity of the disease, there is uncertainty regarding the optimal treatment strategy, especially in patients that present with known risk factors. The role of adjuvant anti-myeloma therapy is still under debate, whereas few studies have reported efficacy of novel agents. We aimed to explore clinical characteristics and treatment patterns and to identify predictors for relapse and progression to myeloma in a real world setting. Methods: Consecutive patients, diagnosed and treated for solitary plasmacytoma in 13 centers, between 2008 and 2019 (defined by the IMWG criteria) were identified, based on medical centers patient registries and pathological reports. Patient's medical charts were reviewed, and data regarding patient and disease characteristics, treatment regimen, and clinical endpoints, focusing on response to treatment and time to disease progression were documented. The treatment response categories were defined according to the IMWG criteria. Results: 62 patients (pts) were identified. Baseline characteristics and workup are detailed in the table. Median follow-up was 39 months (mo) (IQR: 13.5, 63.3). Fifty nine pts (95.2%) were treated with radiotherapy, with a median dose of 45.0 Gy (range: 30-54 Gy); radiotherapy dose was 45-54 in 31 pts, < 45Gy in 11 pts. Twenty pts (33.9%) underwent surgery in addition to radiotherapy, 3 more pts underwent a surgery alone. The median time to radiotherapy since diagnosis was 2.7 months (range: 1day-18.2 months), 8 pts received any anti-myeloma therapy for treatment of plasmacytoma including Melphalan/dexamethasone (n=1), bortezomib based induction followed by ASCT (n=2), VD/VTD (n=2) and KRD (n=1). Among 25 patients with evaluable post-therapy PET-CT response (performed 12 months post radiotherapy), 26% had no remaining FDG uptake, 20% had a 50% or greater decrease in FDG uptake. Among 40 patients with CT or MRI post therapy assessment, 20% had disappearance of SPC, 27% had ≥50% reduction, 7% had During the follow-up period, 16 pts (25.8%) experienced evolution to MM (15 pts had bony and 1 soft tissue plasmacytoma in diagnosis). Among patients with bone SPC (n=49), 30.5% evolved to MM. A total of 6 pts had a recurrence of SPC (5 pts had a bony and 1 patient upper aerodigestive plasmacytoma in diagnosis). 5 pts died (3 without recurrence or evolution to MM). Median time to plasmacytoma recurrence in pts that achieved CR was 36.7 mo (range: 3 -67.9 mo); Median time of evolution to MM was 37.5 mo (range: 6.7-87.2 mo). Progression free survival (PFS) was 67.7 mo for all pts (Fig1A), 48 mo for bone SPC and was not reached for non-bone SPC (p=0.11) (Fig1B). Median overall survival was not reached. Overall survival at median follow-up was 93.6%. Notably, all 8 pts who were treated with anti-myeloma therapy had a bony plasmacytoma and received radiotherapy in addition. None of these pts had recurrence of plasmacytoma or evolution to MM. Of the 11 pts that had SPC in an upper aerodigestive tract site, none evolved to MM; 10 of these pts were treated with only radiotherapy, one had a plasmacytoma recurrence in the same site. Conclusions: We present real world data of a multicenter patient cohort with SPC. As previously suggested, prognosis is more favorable for none bone SPCs. Though numbers are modest, our analysis suggests a benefit of the early addition of systemic therapy to standard radiotherapy for patients with solitary bone plasmacytoma. Disclosures Yael: Janssen: Consultancy; Amgen: Consultancy, Research Funding; Neopharm: Consultancy; Takeda: Consultancy; Madison: Consultancy; VBL Therapeutics: Employment.

BACKGROUND: Real-world data can provide important information on the safety profile for recommended treatment options, but these data are collected infrequently. The ongoing post-authorization safety study (PASS) MM-034 (NCT03106324) is a prospective non-interventional study in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible. This study allows for the collection of robust safety data for currently recommended regimens for the management of these pts. Global guidelines recommend lenalidomide (LEN) regimens, such as LEN plus dexamethasone (DEX; Rd) and LEN plus bortezomib (BORT) plus DEX (Vd), and BORT regimens, including BORT plus melphalan plus prednisone (VMP). METHODS: Transplant-ineligible adult pts with NDMM initiating therapy in centers throughout Europe are being enrolled in the ongoing MM-034 trial. Pts receiving any first-line regimen are eligible, but the decision for which treatment regimen will be used must be made prior to study inclusion. The primary endpoint is the incidence of cardiovascular events. Secondary endpoints include the incidence of renal impairment, infections, and second primary malignancies. In this analysis, the safety profiles of Rd, Vd, and VMP were compared. RESULTS: As of April 12, 2019, 145 Rd, 53 Vd, and 83 VMP pts were enrolled in the study (evaluable cohort). At the time of data cutoff, treatment was ongoing in 64.8% of Rd pts, 41.5% of Vd pts, and 61.4% of VMP pts. Median age was 79 years in Rd pts and 75 years in both Vd and VMP pts. The proportion of pts with ISS stage III disease was higher in the Vd group (24.8% Rd vs 32.1% Vd vs 24.1% VMP), and more pts in the VMP group were male (49.7% Rd vs 58.5% Vd vs 65.1% VMP). Adverse events (AEs) of all grades confirmed the expected side effects. Any-grade neutropenia occurred in 7.6%, 11.3%, and 13.3% of Rd, Vd, and VMP pts, respectively, and thrombocytopenia occurred in 6.2%, 5.7%, and 12.0%, respectively. However, any-grade febrile neutropenia was seen only in the VMP group, at 2.4%, but not in the other 2 groups. Any-grade polyneuropathy was reported in 1.4% of Rd pts, but in 18.9% of Vd pts and 19.3% of VMP pts. Any-grade infections of all kinds occurred in 28.3% of Rd pts, 41.5% of Vd pts, and 20.5% of VMP pts, with pneumonia in 3.4%, 11.3%, and 2.4% of Rd, Vd, and VMP pts, respectively. Any-grade thrombosis was reported in 4.8% of Rd pts and 3.8% of Vd pts and in no VMP pts. Grade 3/4 AEs occurred in 42.8% of Rd pts, 52.8% of Vd pts, and 43.4% of VMP pts. Grade 3/4 neutropenia was reported in 4.8%, 9.4%, and 8.4% of Rd, Vd, and VMP pts, respectively, and thrombocytopenia in 2.8%, 0%, and 8.4%, respectively. Grade 3/4 infections were lower in Rd pts (6.9% vs 24.5% Vd and 12.0% VMP); pneumonia, the most important of these, was reported in 0.7%, 5.7%, and 2.4% of Rd, Vd, and VMP pts, respectively. Grade 3/4 peripheral neuropathy was not seen in the Rd group; however, it was reported in 3.8% of Vd pts and 2.4% of VMP pts. Grade 3/4 venous thrombosis was reported in only 0.7% of Rd pts, with no events reported in the Vd and VMP groups. CONCLUSIONS: The results from this analysis, along with those from a previous analysis of cardiovascular events in the LEN-treated and non-LEN treated cohorts of pts from the European PASS MM-034 study (De Stefano, EHA 2019), provide real-world evidence for the safety profile of Rd as first-line therapy and support the role of Rd in the treatment of pts with NDMM who are transplant ineligible. Disclosures Cavo: celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tromp:Janssen: Other: Grant. Dhanasiri:Celgene Corporation: Employment, Equity Ownership. Kueenburg:Celgene: Consultancy. Rosettani:Celgene International: Employment. Martin:Celgene: Employment. Pozzi:Celgene: Consultancy. Bacon:Celgene: Employment, Equity Ownership. Gamberi:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Front-line treatment (of any type) was at the discretion of the investigator.

Background In February 2019, the National Medicinal Products Administration (NMPA) approved the first China-manufactured rituximab (RTX) biosimilar, HLX01, for the treatment of non-Hodgkin's lymphoma in accordance to the development of biosimilar guidelines with stepwise approach demonstrating bioequivalence. HLX01 was also developed as a novel drug for rheumatoid arthritis (RA) since the indication has not been approved in China. Studying pharmacokinetics (PK) in healthy volunteers as the most sensitive population is not ethically acceptable due to the safety concerns associated with rituximab. The NMPA approval was based on a comprehensive data package of extensive analytical characterization, non-clinical studies, clinical trials and the population PK (PopPK) model. Here, we report the Phase 3 confirmatory study aimed to establish equivalence in safety and efficacy of HLX01 and RTX in patients with diffuse large B-cell lymphoma (DLBCL) and the PopPK model derived from the PK data of HLX01 and RTX in RA compared the PK data in DLBCL and the Caucasian RTX data in RA. Methods In this multicenter, randomized, double-blind, parallel active-controlled, Phase 3 study (NCT02787239), treatment-naïve adults aged 18-80 years with histologically confirmed CD20+ DLBCL were treated with cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) and randomly assigned at 1:1 ratio to co-administer with HLX01 (H-CHOP) or RTX (R-CHOP) every 21 days cycle treatment. The primary efficacy endpoint was the best overall response rate (ORR) for HLX01 and RTX over 6-cycle therapy. The therapeutic equivalence was concluded if 95% confidence interval (CI) of the difference in best ORRs between the two treatments fell within the pre-specified range of ±12%. Additional endpoints included long-term efficacy outcomes, safety and immunogenicity profiles and sparse PK samplings for peak and trough levels comparison. The PopPK model was developed from the randomized, double-blind PK study (NCT03355872) of HLX01 and RTX in 196 patients with moderately to severely active RA (serum sample=4289) using non-linear mixed-effect modeling (NONMEM®) and the first-order estimation with interaction (FOCEI) method. The PK and PK-pharmacodynamic relationship being characterized with various covariates were tested on forward addition (p Results The best ORRs [95% CI] within 6 cycles therapy were 94·1% [89·77%, 97·04%] in H-CHOP and 92·8% [88·19%, 96·00%] in R-CHOP with the ORR difference (1·4% [−3·59%, 6·32%], p=0·608) fell in the pre-specified equivalent margin. Long-term efficacy and safety profiles, including the incidence of treatment-emergent adverse events (p=1·000) and serious adverse events (p=0·752), were similar in two treatment groups (Table 1). The best model fit for the PopPK was a two-compartment model with first-order elimination. The estimated clearance (CL), central volume (Vc), peripheral-compartment volume and clearance-of-distribution from the central-to-peripheral-compartment were 27·32%, 16·56%, 21·61%, and 40·79%, respectively. The correlation between CL and Vc was 0.02239. The observed concentrations and simulations for the corresponding model predicted all subjects in the dataset with no significant difference in area under the curve from zero to infinity between two clinical studies of HLX01 and RTX. The PK results were also similar to the existing model in Caucasian. Conclusion HLX01 demonstrated equivalent safety and efficacy to the reference RTX with no clinically meaningful differences in CD20+ DLBCL. The PopPK model successfully proved the PK similarity between HLX01 and RTX in patients with RA or DLBCL with no racial differences. Based on the totality of evidence with the results from this Phase 3 study and PopPK modeling, China NMPA approved HLX01 as the first China RTX biosimilar with the potential to provide alternative treatment option for patients. To the best of our knowledge, we are the first reporting the establishment of biosimilarity with RTX in DLBCL patient population. Disclosures Zhao: Certara Strategic Consulting China: Employment. Hong:Shanghai Henlius Biotech, Inc.: Employment. Ma:Shanghai Henlius Biotech, Inc.: Employment. Cheng:Shanghai Henlius Biotech, Inc.: Employment. Ting:Shanghai Henlius Biotech, Inc.: Employment. Li:Shanghai Henlius Biotech, Inc.: Employment. Jiang:Shanghai Henlius Biotech, Inc.: Employment. Liu:Shanghai Henlius Biotech, Inc.: Employment. Liu:Shanghai Henlius Biotech, Inc.: Employment. Zhang:Shanghai Henlius Biotech, Inc.: Employment. Chai:Shanghai Henlius Biotech, Inc.: Employment. Yao:Shanghai Henlius Biotech, Inc.: Employment. Luk:Shanghai Henlius Biotech, Inc.: Employment.

Introduction: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in patients undergoing induction chemotherapy for acute myeloid leukemia (AML). During induction chemotherapy for AML patients, antifungal prophylaxis (AP) has been associated with a decreased incidence of IFIs and increased survival. However, some centers do not use AP, as it is unclear whether it improves outcomes in settings where the incidence of IFIs is low ( Methods: AML patients ≥18 years of age who underwent induction chemotherapy between 1/1/07 and 4/1/19 were identified by pharmacy records. Data was verified and extracted by two members of the research team. Primary endpoints were in-hospital mortality during induction chemotherapy and rates of fungal infections within 90-days after induction. Secondary endpoints were 30-day post induction and 90-day post-discharge survival, rates of proven/probable IFI by application of the Mycoses Study Group definitions, diagnostic resource utilization and tolerability. Categorical variables were compared with x2 or Fisher's exact tests and continuous variables with independent samples t-test or the non-parametric Mann-Whitney test as appropriate. Post-induction survival was also analyzed with Kaplan-Meier (KM) curves. Results: 108 adult AML patients were retrospectively reviewed. Fifty-six received AP during induction and 52 did not, without significant differences in demographic or leukemia-specific factors. AP was associated with numerically less fungal infections (9/56 (16%) vs. 14/52 (27%), P=0.169) and proven/probable IFIs (3/52 (6%) vs. 0/56, P=0.1). AP was also associated with lower in-hospital (11/52 (21%) vs. 4/56 (7%), P=0.035) mortality. Clinicians obtained more electrocardiograms (median 4 vs. 1.5, P Implementation of a dedicated inpatient malignant hematology service led to standardization of practices including AP (24/76 (32%) vs. 32/32 (100%), P Before implementation of this service, AP was associated with numerically lower in-hospital mortality during induction (3/24 (13%) vs. 11/52 (21%), P=0.366), and significantly improved 30-day post-induction survival (Fig. 1, log-rank P=0.042). Conclusions: In a setting where mold infections are rare, AP in patients undergoing induction chemotherapy for AML was associated with improved survival, empiric or targeted antifungal treatment, and a signal for decreased frequency of fungal infections, without substantial increases in utilization of diagnostic resources. This study is limited in its single-center retrospective study design, the overall small number of patients, and is confounded by simultaneous changes in practice, especially with the implementation of a dedicated malignant hematology service. Notably however there was improved 30-day mortality in patients on AP versus those not on AP prior to the implementation of the malignant hematology service. Our findings indicate that outcomes are optimized when adult patients with AML receive their care by a dedicated malignant hematology team, with implications for low-volume institutions and community practices, where AML inductions are not always performed under the care of malignant hematology specialists. Our results suggest that AP and admitting or transferring adult AML patients to a center with a dedicated malignant hematology service, when feasible, may lead to better outcomes. Figure 1 Disclosures Farmakiotis: Astellas: Research Funding; Viracor-Eurofins: Consultancy, Research Funding.

Background: The incorporation of crossover in randomized controlled trials is accepted as an ethical obligation, especially in cancer clinical trials. The more common type of crossover is unidirectional, which allows patients assigned to the control arm (either placebo or standard of care) to switch to the experimental arm. In contrast, bidirectional crossover includes the switching of patients from the experimental arm to the control arm. Integrating crossover into the initial study design may have advantages in patient recruitment, and incorporating crossover after initial positive results fulfills ethical requirements. However, crossover can also contribute to confounding major endpoints of studies, such as overall survival or the second progression-free survival interval. For this reason, it is important to investigate and identify potential trends of crossover in clinical trials testing novel therapies. The development of new treatments for hematologic malignancies is promising, and as such, makes these trials susceptible to crossover. Trends in crossover of clinical trials for hematologic malignancies have not yet been studied. Methods: Data about cancer clinical trials were extracted from clinicaltrials.gov. The search query was limited to completed phase III studies in adult populations. Location was limited to the United States. No date range or funder type was specified. The following search query was used: recruitment status: "completed;" age: "adult (18-64)," "older adult (65+);" sex: "all;" country: "United States;" study phase: "phase 3." These criteria were then applied in individual searches for clinical trials related each hematologic malignancy. The following terms were used in the "disease" search field: "acute lymphoid leukemia," "acute myeloid leukemia," "multiple myeloma," "lymphoma," "chronic myeloid leukemia," and "chronic lymphocytic leukemia." Repeat clinical trials obtained through separate searches were excluded. Studies were then excluded if they were not randomized controlled trials (RCTs) with the primary purpose of treatment, and if they did not test cancer-related interventions. Results: A total of 184 unique clinical trials were identified, of which 156 were RCTs with the primary purpose of treatment. Only 149 trials tested cancer-related drugs, biologicals, or procedures. Of those, 60 trials contained 2 experimental arms, and 89 trials contained 3 or more experimental arms. 6 of the 60 (10%) 2 arm trials permitted crossover, and 4 of the 89 (4.5%) 3+ arm trials permitted crossover, for a total of 10 trials with crossover. The start dates of these trials ranged from 2000-2012. 3 trials (30%) were bidirectional, and 7 (70%) were unidirectional. The identified clinical trials with crossover belonged to only 3 of the original 6 hematologic malignancies included in the original search query: multiple myeloma, lymphoma, and CML (Table 1). Conclusions: The proportion of identified clinical trials with crossover to those without is extremely small. Crossover in clinical trials studying hematologic malignancies does not appear to be a widespread practice. Multiple myeloma contains the most trials with crossover compared to other hematologic malignancies. Even though statistical approaches to mitigate confounding exist, crossover can still skew accurate reporting of the impact of experimental therapies on overall survival. Examining trends among the trials with crossover will hopefully lead to improved correction methods and better estimates of treatment benefit. Disclosures No relevant conflicts of interest to declare.

Background There is an unmet need in treating patients (pts) with AML who are unfit for intense chemotherapy due to advanced age and/or presence of co-morbidities. This population often has poor risk disease features. Low-dose cytarabine (LDAC) monotherapy is a SOC therapy for elderly, unfit pts. The CR rate with LDAC is 18% as reported in the MRC AML14 study, with a median OS of approximately 4-5 months (Burnett et al, 2007). To improve the OS of this challenging patient population, an increase in the CR rate and longer response duration is essential. The receptor tyrosine kinase AXL represents a novel therapeutic target promoting AML cell proliferation and survival and is a negative regulator of anti-tumor immunity. Bemcentinib is a first-in-class, highly selective, potent, oral AXL kinase inhibitor with a favorable safety profile. We have previously reported bemcentinib monotherapy anti-leukemic activity in r/r AML and MDS pts. Bemcentinib treatment was also reported to induce T- and B-cell receptor diversification as well as clonal stabilization have also been reported. We report on cohort B2 of an open-label Phase II study (BGBC003), designed to explore the safety and efficacy of bemcentinib given in combinations with LDAC to pts with AML unfit for intensive chemotherapy. Secondary objectives are OS and exploratory biomarker analyses. Methods In Part B2, AML pts unfit for intensive chemotherapy received bemcentinib at the RP2D (200mg PO/d) + SOC LDAC SQ for 10 days in 21-day cycles (dosing according to standard practice). Primary endpoints include identifying safety and tolerability of combination, and secondary endpoints include OR, RFS and OS. Plasma protein biomarker levels including soluble AXL (sAXL) were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at baseline and following treatment. Results A total of 16 pts were enrolled. Median age was 76 years (range 66-83). Of the 13 pts with available cytogenetic results, 5 pts (38%) had a poor risk cytogenetic profile, 7 (54%) were intermediate, 1 (8%) favorable. Bone marrow results showed a median of 35% myeloblasts at screen (range 3-96%). As of July 2019, 15 pts were evaluable for response by BM aspirate on or after C2D1. Six of the evaluable pts had objective responses (ORR 40%, 4 CR/CRis + 2 PRs). Five of the responses (4 CR/CRi + 1 PR) were durable, ranging from 3.4 to 11.7 mos, all still ongoing. All 5 pts with durable responses were >75 years old (range: 76-83). Survival of these 5 pts ranged from 8.8-12.4 months at cut-off, with no relapse or significant events yet reported. Of these 5 pts, 1 had relapsed disease, 3 had secondary AML, and 2 had unfavorable cytogenetics. Additionally, 3 pts (aged 71-78 years old) had durable stable disease lasting approximately 4 mos, with 1 remaining on study. Of the 3 pts, 1 had newly-diagnosed and 2 refractory AML, and at least 1 had secondary AML. The RFS and OS data is not yet mature and will be reported at a later stage. The combination was generally well tolerated with expected and manageable AE profile, with pts continuing the combination up to >19 cycles at cut-off. All pts experienced at least one AE regardless of relation to study treatment, the most common being diarrhea (7/16, 44%) and anaemia (6/16, 38%). The most common treatment-related AEs (TRAEs) were diarrhea (4/16, 25%), electrocardiogram QTc prolongation (3/16, 19%) and decreased platelet count (3/16, 19%). Of these TRAEs, 1 drug interruption and 1 withdrawal were reported; none of these events were reported as SAEs. SAEs occurring in >1 patient were febrile neutropenia (4/16, 25%; 1 related to study drug), and pyrexia (2/16, 12.5%; not related to study drug). These SAEs are typically observed in AML. Conclusions The combination of bemcentinib + LDAC induced a response rate of 40% in pts with newly-diagnosed and relapsed AML. CRs were durable, lasting more than 11 mos in some pts. Durable responses were seen in elderly AML pts including those with adverse disease features. AEs reported were as expected in this population. The DOR of the combination has the potential to improve the OS in this population. Further biomarker exploration will be reported at the conference. Encouraging results in this elderly pt population will lead to further clinical development with this treatment combination. Disclosures Loges: BerGenBio ASA: Honoraria, Other: Advisory Board, Travel Support, Research Funding. Heuser:Synimmune: Research Funding; Bayer Pharma AG, Berlin: Research Funding. Paschka:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Takeda: Other: Travel expenses; Agios: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Amgen: Other: Travel expenses; Abbvie: Other: Travel expenses. Micklem:BerGenBio ASA: Employment, Equity Ownership. Holt:BerGenBio ASA: Employment. Lorens:BerGenBio ASA: Employment, Equity Ownership. Shoaib:BerGenBio ASA: Consultancy. Aly:BerGenBio ASA: Consultancy. Hanekom:BerGenBio ASA: Consultancy. Fiedler:Amgen, Pfizer, Novartis, Jazz Pharmaceuticals, Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, Pfizer, Abbvie: Other: Support in medical writing; Amgen, Jazz Pharmaceuticals, Daiichi Sanchyo Oncology, Servier: Other: Support for meeting attendance; Amgen: Research Funding. Cortes:Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Gjertsen:Research Council of Norway: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ACTII AS: Equity Ownership; Seattle Genetics: Consultancy; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Helse Vest Health Trust: Research Funding; ERA PerMed: Research Funding; Haukeland University Hospital / University of Bergen: Employment; KinN Therapeutics AS: Equity Ownership; EU Horizon 2020: Research Funding; Daiichi Sankyo: Consultancy; BerGenBio: Consultancy; The Norwegian Cancer Society: Research Funding.

Background: Myelodysplastic syndrome (MDS) therapeutic decisions have been traditionally based on the International Prognostic Scoring System (IPSS) (Greenberg et al, Blood 1997) and IPSS-R (Greenberg et al, Blood 2012). Recently, next-generation sequencing genetics has been incorporated into management of MDS, however its use is limited in routine clinical practice. Current prognostic models do not allow the identification of patients with low risk disease (low or intermediate-1 IPSS) and poor prognosis, who could benefit from an early intervention. Garcia-Manero et al (Leukemia 2008) described a specific prognostic scoring system for this subgroup of patients (LR-PSS) based on age ≥60 years, hemoglobin Aim: To analyze the prognostic value of Low Risk Prognostic Scoring System(LR-PSS) in a population of lower risk MDS patients (very low, low and intermediate IPSS-R) analyzing as endpoints overall survival (OS) and leukemia free survival (LFS). Methods: A total of 890 consecutive patients with MDS (01/1992-7/2018) diagnosed at the Catalan Institute of Oncology in Barcelona were included in the study. 539 (60%) had available cytogenetics and therefore, IPSS-R could be assessed. 474 (88%) patients were classified as very low, low and intermediate IPSS-R and were included in the study. Results: 178 (37.6%) patients were classified as very low, 219 (46.2%) low and 77 (16.2%) intermediated IPSS-R risk MDS. Median age at diagnosis was 73 years (range 32-101). 332 (70%) were male. According to the 2008 WHO classification, 2.5% CRDU, 7.4% RA, 42.2% RCMD, 13.7% RAEB‐1, 3.6% RAEB‐2, 26.4% CMML and 4.2% MDS‐U with isolated 5q deletion. At diagnosis, median hemoglobin, platelet and bone marrow blast were 11.6 g/dL (5.5-17.1), 157 x109/L (1-1492) and 2 % (0-17), respectively. 84 (17.7%) patients had unfavorable LR-PSS cytogenetics at diagnosis. Median follow up time for survivors was 5.4 years (range 0.25-23.8). At the time of last follow up, 58.4 % (277) had died and 71 (15%) had progressed to acute myeloid leukemia. When the LR-PSS was applied to the very low, low and intermediate IPSS-R subgroups, three well-differentiated prognostic categories could be identified: 103 patients (21.7%) category 1 (scores 0-2); 330 (69.6%) patients category 2 (scores 3-4) and 41 (8.7%) patients category 3 (scores 5-7) with significant different OS and LFS. Median OS for categories 1, 2 and were 7.1 years (95% CI 4.9-9.2), 5.7 years (95% CI 4.7-6.7) and 2.8 years (95% CI 2.1-3.6), p Summary/Conclusion: When applied to a low risk (very low, low and intermediate) IPSS-R cohort of MDS population, LR-PSS identifies a subgroup of patients with a significantly worse prognosis who could benefit from an early treatment intervention. Disclosures Sureda: Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy; Roche: Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau.

Introduction: Mosunetuzumab (M; RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Clinical data from GO29781 (NCT02500407), a Phase I/Ib study in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) pts, indicate that M has promising efficacy and safety (Budde et al. ASH 2018; Bartlett et al. ASCO 2019). We report the characterization of exposure-response (E-R) relationships for safety and efficacy to inform clinical dose/regimen finding. Methods: DATA: Data from Group A (0.05 to 2.8mg q3w dosing) and Group B (0.4/1/2.8 to 1/2/27mg Cycle 1 Day 1/8/15 step-up dosing, followed by q3w dosing) were analyzed. E-R for safety was assessed in 142 evaluable pts by dosing Group. E-R for efficacy was assessed in 130 evaluable pts by aggressive (a) (n=83, primarily DLBCL and transformed FL) and indolent (i) (n=47, primarily FL) NHL histologies. PHARMACOKINETIC (PK) ENDPOINTS: Pt-specific PK exposure metrics, including AUC and Cmax, were derived using a preliminary two-compartment population PK model with time-dependent clearance. Due to the presence of residual rituximab (R) at baseline from prior treatments, an additional exposure metric of average CD20 receptor occupancy (RO%) of M was derived based on the serum PK and binding affinity (KD) of both agents to assess the impact of target binding competition over time. E-R ANALYSES: Objective response rate (ORR), complete response rate (CRR), and adverse event (AE) rates, including cytokine release syndrome (CRS) and neurological AEs (NAE), were summarized by exposure-tertiles and the E-R relationships modeled by logistic regression (linear or Emax models). Response rates and E-R were further assessed in subgroups by RO% tertiles and baseline factors, such as the number of prior lines of therapy, refractory status, lactate dehydrogenase level, and tumor burden, and modeled by multivariate logistic regression. Results: R was present at modest levels at baseline in aNHL pts (median, 3 µg/ml, 33% of pts below quantitation limit [BQL] of 0.5µg/ml) but minimally in iNHL pts (median, Conclusions: E-R analyses indicate promising therapeutic benefit/risk of M in R/R NHL pts. Step-up dosing mitigated CRS-related toxicities, resulting in a broad therapeutic window of M that enables further dose escalation to maximize efficacy. The lack of E-R for safety was contrasted by a steep E-R for efficacy whereby higher M exposures overcome target binding competition in pts with residual R. Our analyses provide useful guidance for the dosing strategy of CD20-targeting T-cell bispecifics. Disclosures Li: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bender:Genentech, Inc.: Employment, Equity Ownership. Yin:Genentech, Inc: Employment, Equity Ownership. Li:Pro Unlimited - Genentech, Inc. contractor: Employment; F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Zhang:Genentech, Inc., SSF: Employment. Hernandez:Genentech, Inc.: Employment, Equity Ownership. Kwan:Genentech, Inc: Employment, Equity Ownership. Sun:Harpoon Therapeutics: Employment, Equity Ownership; F. Hoffmann-La Roche Ltd / Genentech, Inc.: Employment. Adamkewicz:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Wang:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lim:Genentech, Inc.: Employment. O'Hear:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Sehn:Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Apobiologix: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Flinn:AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; Kyowa Hako Kirin: Research Funding; Amgen: Consultancy, Honoraria; Yuhan Pharma: Research Funding; Genentech, Inc.: Research Funding; MSD: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Li:Genentech, Inc. / F. Hoffmann-La Roche Ltd: Employment. Wei:Genentech, Inc./F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. OffLabel Disclosure: Mosunetuzumab (RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Background: The treatment indications for venetoclax in CLL are broadening quickly. While the initial approval was for relapsed patients with del 17p (Stilgenbauer S, et al. JCO 2018), it has subsequently been extended to all patients (Seymour J, et al. NEJM 2018, Fischer K, et al. NEJM 2019). The duration of therapy with each approval has evolved as well, from continuing therapy until progression/toxicity to 1 year in front-line CLL. The limited durations of therapy were applied to all patients based on trial design and were not dependent on response to treatment. Undetectable minimal residual disease (U-MRD) with venetoclax is associated with improved progression-free survival (PFS), both as a single agent and in combination with rituximab (Stilgenbauer S, et al. JCO 2018, Seymour J, et al. NEJM 2018). Early phase data suggest that patients who discontinue venetoclax after achieving MRD negativity can be monitored off therapy and successfully retreated upon relapse (Seymour J, et al, Lancet Onc 2017). However, patients who discontinue therapy with persistent residual disease have a higher incidence of relapse (Kater A, et al. JCO 2019). Together, these data suggest that the duration of venetoclax therapy should be individualized, based on the depth of response one achieves and not a fixed duration schedule. Therefore, we propose a prospective clinical trial, utilizing MRD assessment with a next generation sequencing (clonoSEQ®) assay to guide clinical decision making in patients with CLL receiving venetoclax-based regimens. Methods: This is a multicenter, phase II clinical stopping trial for 80 venetoclax-treated CLL patients. The clonoSEQ® assay is used to assess MRD, and patients who achieve U-MRD (defined as Patients are eligible if they have CLL/SLL and are currently receiving venetoclax monotherapy or in combination with anti-CD20 (front-line or relapsed). Following informed consent for screening, the ClonoSEQ® ID test will be performed on a sample containing active disease, either fresh (blood or bone marrow) or stored specimens (3-5 bone marrow aspirate slides, 3-5 FFPE slides from a pathologically involved lymph node, or 1 mL involved peripheral blood/bone marrow aspirate). Following ClonoSEQ® ID testing, patients will be evaluated for MRD in the peripheral blood by the ClonoSEQ® MRD assay at two time points, at least 28 days apart. Patients who have received at least 6 months of venetoclax and achieve U-MRD will sign an intervention informed consent and enter a period of treatment-free observation. Close monitoring with serial MRD assessments on the peripheral blood will occur every three cycles for 36 cycles (1 cycle = 28 days; Figure 1). Patients who remain MRD undetectable or become MRD positive will continue to be observed until clinical progression warranting therapy by iwCLL criteria. If a patient develops a clinical indication for treatment, they are recommended to be retreated with the same venetoclax-based regimen. Re-treated patients will undergo standard response/toxicity assessments and serial assessment of MRD status every three cycles. Response and MRD assessments for retreated patients will continue for a total of 12 cycles or to the end of 36 cycles from the time of treatment free observation, whichever occurs first. The primary endpoint of the study is the proportion of patients able to remain off venetoclax-based therapy at 12 cycles following treatment discontinuation. The secondary endpoints include (1) the cumulative incidence of MRD positivity (2) cumulative incidence of retreatment during treatment-free observation (3) PFS and OS as measured from start of treatment-free observation. Should a patient require re-treatment, endpoints of interest include ORR, CR rate, MRD negativity rate, and adverse event profile for venetoclax-based therapy re-treatment. Healthcare outcomes endpoints including economic analysis of cost savings for patients discontinue therapy and quality of life assessment pre- and post-venetoclax discontinuation will be evaluated. Disclosures Ujjani: AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Gilead: Consultancy; PCYC: Research Funding; Astrazeneca: Consultancy; Atara: Consultancy; Pharmacyclics: Honoraria. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Shadman:TG Therapeutics: Research Funding; Gilead: Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; Pharmacyclics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; AbbVIe: Consultancy, Research Funding; Merck: Research Funding; Atara: Consultancy; Verastem: Consultancy; Mustang Biopharma: Research Funding; Bigene: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Acerta: Research Funding; Emergent: Research Funding. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria. Zelenetz:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mato:Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding.

Background: Patients (pts) with myelofibrosis (MF) suffer from a wide range of possibly debilitating disease manifestations (e.g. splenomegaly, weight loss, fatigue, night sweats, pain etc) resulting in severe symptom burden and quality of life decrement. Compared to INT-2/HIGH IPSS risk categories, lower risk pts display a less severe disease burden at diagnosis; nonetheless, with no active therapy, disease severity increases over time in all risk categories (Mesa et al, Leuk Res 2013). ROMEI (CINC424AIT04-Ruxolitinib Observational study in Myelofibrosis treated patiEnts in Italy) is a prospective observational study focused on real-life management of MF pts treated with ruxolitinib (RUX). The prospective assessment of the Myeloproliferative Neoplasm 10 (MPN 10) total score over time and the EQ-5D-5L and its related general health EQ-VAS values over time were included as primary endpoints and changes in spleen length were instead included as secondary endpoint. Aims: To analyze the extent lower-risk MF pts treated with RUX may differentiate from higher-risk pts treated with RUX in terms of disease characteristics at treatment start, toxicity and response. A sub-analysis of the ROMEI trial was performed to evaluate differences in disease burden (i.e symptoms according to MPN-10, general health status according to EQ-VAS and spleen length) at RUX start and its modification after 24 weeks (wks) of treatment between pts with different BL IPSS category. Methods: Out of 215 enrolled pts, 183 (96 male) were evaluable for this sub-analysis: 34 INT-1, 89 INT-2 and 60 HIGH risk pts based on IPSS. BL (BL) pts characteristics are shown in table 1. Pts started RUX according to Summary of Product Characteristics; MPN-10 scores and EQ-VAS values were collected at BL and at wks 4, 8, 12 and 24 after treatment start; spleen length by manual palpation was assessed at the same time points. Differences in IPSS subgroups were compared by means of analysis of variance (ANOVA) applied on rank transformed data in case of non-normal distribution. The BL value was included in the models on scoring changes. Results: MPN-10. In the overall cohort, we observed an improvement of MPN-10 score upon RUX start from 34.86±17.90 (range 0-88) at BL to 21.55±15.25 (range 0-70) at wk 24. No statistically differences were observed on MPN-10 total score between IPSS risk categories both at BL (P=0.83) and at wk 24 (P=0.53). Furthermore, the improvement in pts' symptoms evaluated by means of change of MPN-10 total score between wk 24 and BL resulted similar between the different IPSS risk categories (P=0.87). EQ-VAS. In the overall group, EQ VAS values increased in mean from 59.88±20.23 (min; max: 0; 100) at BL to 67.36±18.57 (min; max: 10; 100) at wk 24. No differences between IPSS risk category were observed at BL (P=0.23, table 1).After 24 wks, EQ VAS was, in mean, 73.70±16.74 in INT-1 risk, 67.78±18.59 in INT-2 risk and 62.45±18.93 in HIGH risk with statistically differences between IPSS risk category (P=0.02) and, in particular, between HIGH and INT-1 risk (P=0.02). Difference between IPSS risk category was observed also when considering the change of EQ VAS between wk 24 and BL (P=0.02): the improvement in pts' health status resulted statistically lower in pts with HIGH compared to INT-1 (P=0.01) while no difference between INT-2 and INT-1 risk was observed (P=0.07). Spleen length. Among evaluable pts, spleen length at BL seemed to increase as the IPSS risk category increased: 7.84±5.64 cm in INT-1 risk, 8.40±5.08 cm in INT-2 risk and 9.17±6.24 cm in HIGH, but no statistical difference was found between the groups (P=0.57). At week 24 mean spleen length decreased in all subgroups: 4,53±5.99 cm in INT-1 risk, 3.90±4.29 cm in INT-2 risk and 5.39±6.52 cm in HIGH risk but again with no statistical difference between groups (P= 0.77). Furthermore, the change of palpable spleen length between wk 24 and BL resulted similar between IPSS risk categories (P=0.55). Conclusion: Our sub analysis suggests that disease burden can be very disabling even in INT-1 pts and comparably as in higher-risk categories. We also demonstrate that the EQ-VAS questionnaire may detect and quantify a wide range of symptoms not adequately included in IPSS risk stratification. Despite improvements in symptoms and splenomegaly were comparable across age groups, general health status improvement was significantly better in INT-1 pts. Further analysis will be available at the meeting. Disclosures Palandri: Novartis: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Celgene: Honoraria; Incyte: Honoraria. Palumbo:Teva: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Hospira: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Liberati:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Clinical trial support; Janssen: Honoraria. Pane:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: research founding; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Tiribelli:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Foà:Celltrion: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Elli:Novartis: Membership on an entity's Board of Directors or advisory committees. Caocci:Novartis: Honoraria; Celgene: Honoraria. Morelli:Novartis: Employment. Passamonti:Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau.

Introduction UK and Ireland clinicians gained non-trial access to ibrutinib for relapsed / refractory CLL through a named patient scheme (NPS) for 7 months in 2014, and the UK CLL Forum has been following a cohort of 315 NPS patients treated with ibrutinib at 66 UK and Ireland hospitals. We now update this dataset with up to 5 years follow-up. Results The primary end-points of the study were Discontinuation Free Survival (DFS) and Overall Survival (OS). Of the original 315 patients, 213 have stopped ibrutinib and 159 patients have died, with all living patients having a survival update in 2019. With 55.6 months median follow-up, median DFS was 33.5 months (95% CI: 28.4-29.3) and median OS was 55.9 months (95% CI: 42.5-N/A) (Figure 1A and 1B). Four years after starting ibrutinib, 37.0% of patients were still taking ibrutinib and 52.4% were still alive. Both DFS and OS were inferior for older (age > median) and PS 2+ patients. Patients with 17p- have inferior DFS and OS compared to patients with other defined cytogenetic aberrations (13q-, 11q-, t(12)) and more patients with 17p- compared with non-17p- stopped ibrutinib for progressive CLL (PD) (26.4% vs 18.8%; p=0.01) and Richter's Syndrome (12.1% vs 8.3%; p=0.05). First relapse patients had more than a 3 fold lower rate of ibrutinib discontinuation due to CLL progression (7.1% versus 24.5%; two-tailed Fisher's exact test; p=0.001) compared with patients receiving ibrutinib at later lines of therapy, although DFS and OS for these groups were similar. With multivariable analysis of pre-treatment factors, older age, PS2+, 17p- and >1 prior line of therapy retained significance for earlier ibrutinib discontinuation and age, PS2+ and 17p- associated with inferior OS. To analyze any potential impact of reduced ibrutinib dosing during the first year of therapy, we originally classified all patients alive at 12 months into 4 groups, depending on first-year ibrutinib treatment. Group A: No dose reductions or breaks >14 days; Group B: Dose reductions, but no breaks > 14 days; Group C: Breaks > 14 days but back on ibrutinib by 1 year; Group D: stopped ibrutinib permanently but still alive at 1 year. With extended follow-up, patients dose reduced in year 1 are very likely to have on-going dose reductions beyond the first year (86% patients in group B are still dose reduced beyond 4 years, compared with 12% in group A). Groups A and B retain similar DFS and OS initially, although beyond 2 years the curves separate (Figure 1C and 1D) (DFS HR: 1.62 (1.05-2.50), OS HR: 1.52 (0.86-2.70)). Interestingly, the dose-reduced group do not have a higher incidence of disease progression, (PD A:24.8%, PD B:23.8%), but have a higher chance of discontinuation for all non-PD causes (A:23.6%, B:42.9%). With longer follow-up, patients from groups C and D had significantly impaired OS compared with group A, with 4 year OS 39.4% and 16.7% respectively compared with 76.4% for group A (p Considering all patients who discontinued ibrutinib, stopping for AEs decreased over time (year 1: 57%, 2: 53%, 3: 30%, 4: 21%). Stopping for infection was much more common in the first year (19.5%) compared with years 2 to 4 (8.4%). The risk of stopping ibrutinib due to PD-CLL increases with time (year 1: 11%, 2: 18.6%, 3: 42.5%, 4: 57.6%). Of the PD-CLL patients, treatment with venetoclax had the best OS (n=43; 1 year OS: 77.5%) compared with the 7 treated with rituximab / idelalisib (1 year OS: 42.9%) and 14 treated with other strategies (including palliative care) (1 year OS: 10%). Although this supports the use of venetoclax for disease progression post ibrutinib, there are two potentially significant biases; more palliative patients did not receive venetoclax and patients who relapsed within 1 year of starting ibrutinib, who were potentially more unstable biologically, did not receive venetoclax (unavailable in the UK pre-2016) Conclusions With approaching 5 years of follow-up, around one third of 'real-world' UK / Ireland patients treated with ibrutinib for relapsed / refractory CLL remain on ibrutinib. Our data suggest that younger, better performance status patients who have had fewer prior lines of therapy and no evidence of 17p deletion seem most likely to remain on ibrutinib long-term. Likewise, patients who remain free of adverse events that often associate with dose reductions and treatment breaks, have the best chances of remaining on ibrutinib. Treatment of PD-CLL with venetoclax post ibrutinib shows encouraging results. Disclosures CLL Forum: Roche: Other: Sponsorship of the UK CLL Forum; Abbvie: Other: Sponsorship of the UK CLL Forum; Janssen: Other: Sponsorship of the UK CLL Forum; Gilead: Other: Sponsorship of the UK CLL Forum. Follows:Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; AZ: Consultancy, Honoraria, Speakers Bureau.

Background: Myelofibrosis (MF) is associated with bone marrow fibrosis (BMF), splenomegaly, a high symptom burden, and poor prognosis; the JAK/STAT pathway is the central pathway implicated in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor and the only FDA-approved pharmacotherapy for treatment (Tx) of MF patients (pts), improves splenomegaly, but is unable to control all clinical manifestations of disease. Navitoclax is an orally bioavailable, novel small-molecule that targets and binds with high affinity to multiple antiapoptotic B-cell lymphoma 2 (BCL2) family proteins, including BCL-XL, BCL2, and BCL-W. Preclinical studies have demonstrated cytotoxic activity of navitoclax against myeloproliferative neoplasm-derived cell lines. Herein, the results of a phase 2 study (NCT03222609) evaluating the combination of navitoclax with ruxolitinib in pts with MF are reported. Methods: This phase 2 single-arm, multicenter, open-label study assessed the efficacy and safety of navitoclax combined with ruxolitinib in pts with MF. Eligible pts (≥18 yr, diagnosis of primary MF, post-essential thrombocythemia [PET]-MF, or post-polycythemia vera [PPV]-MF, ECOG 0-2, receiving at least 12 wk of continuous ruxolitinib therapy prior to study Tx initiation) received a starting dose of 50 mg navitoclax once-daily combined with the current stable dose of ruxolitinib (≥10 mg BID). Weekly intra-patient dose-escalation of navitoclax was allowed to a maximum daily dose of 300 mg based on tolerability and platelet count. Tx continued until the end of clinical benefit, unacceptable toxicity, or discontinuation. The primary efficacy endpoint was percentage reduction in splenic volume from baseline. Secondary endpoints included effect on total symptom score (TSS), overall response rate, rate of anemia response, improvement in BMF, and safety profile. Results: As of May 1, 2019, 34 pts (primary MF, n=16; PET-MF, n=5; PPV-MF, n=13) had received ≥1 dose of navitoclax in combination with ruxolitinib. Median age was 68 yr (range 42-86), 68% were male, and 9 pts (26%) had ≥3 prior lines of MF therapy. The median duration of prior ruxolitinib exposure was 745 days (range 134-4549). Of the 34 pts enrolled, 27 (79%) had JAK2 and 7 pts (21%) had CALR mutations. There were no pts enrolled with triple-negative MF. Of 33 pts with available baseline testing, 17 (52%) had high molecular risk, defined by mutations within ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1. The mean baseline platelet count was 231 x 109/L (range 99-706); mean baseline Hgb was 10.8 g/dL; 19 (56%) pts had elevated WBC at baseline (>1.5× ULN). Maximal navitoclax dose of 300 mg was achieved in 23 pts (68%). Of the 25 (74%) pts that enrolled on ruxolitinib doses >10 mg BID, 22 (88%) subsequently had the dose of ruxolitinib reduced to 10 mg BID. At the time of this analysis, 24 pts were evaluable for efficacy, with 20 pts completing ≥24 wk on study and 4 pts with Tx discontinuations prior to 24 wk. At wk 24, 7 of 24 pts (29%) achieved a spleen volume reduction of ≥35% (SVR35) from baseline by MRI as determined by prespecified central review; the median TSS was 7.4 (range 0-23), a 20% improvement from baseline. A SVR35 at any time on study was achieved in 10 pts (42%). Reductions in driver mutation allelic burden of >5% were observed in 10 (42%) pts; 6 pts (25%) had BMF improvement of ≥1 grade. One pt (4%) had an anemia response; the mean Hgb at wk 24 was slightly improved over baseline at 11.3 g/dL. Of the 19 pts with elevated baseline WBC, 16 (84%) reduced to within normal limits during Tx, with a median WBC reduction of 17.7 × 109/L. All pts experienced a Tx-emergent adverse event (TEAE); most common (≥20%) were thrombocytopenia (82%), diarrhea (62%), fatigue (53%), anemia (27%), nausea (27%), contusion (24%), and vomiting (21%). Grade ≥3 TEAEs occurred in 26 pts (77%); most common were thrombocytopenia (n=15, 44%; Grade 4 n=1, 3%) and anemia (n=8, 24%; no Grade 4). Five pts (15%) experienced serious AEs that resolved including anemia, upper abdominal pain, vomiting, chest pain, increased C-reactive protein, and abnormal liver function test (3% each). There were no significant episodes of bleeding and no TEAE-related deaths. Conclusions: Navitoclax in combination with ruxolitinib was well tolerated with clinically meaningful spleen responses, allelic burden reductions, TSS improvements, and encouraging improvements in BMF in pts with MF who have received prior Tx with ruxolitinib. Disclosures Harrison: CTI: Speakers Bureau; Promedior: Honoraria; Roche: Honoraria; Celgene: Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Shire: Speakers Bureau; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Speakers Bureau. Garcia:Genentech: Research Funding; Abbvie: Research Funding. Mesa:CTI: Research Funding; Galena Biopharma: Consultancy; Samus: Research Funding; Genotech: Research Funding; AbbVie: Research Funding; NS Pharma: Research Funding; Baxalta: Consultancy; LaJolla: Consultancy; Shire: Honoraria; PharmaEssentia: Research Funding; Genentech: Consultancy; Celgene Corporation: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Promedior: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; Incyte: Other: travel, accommodations, expenses, Research Funding; Gilead Sciences: Research Funding; Pfizer: Research Funding; Sierra Oncology: Consultancy. Somervaille:Novartis: Consultancy. Komrokji:pfizer: Consultancy; celgene: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Pemmaraju:sagerstrong: Research Funding; celgene: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; samus: Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; incyte: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; affymetrix: Research Funding. Papadantonakis:Agios: Consultancy, Honoraria. Foran:Agios: Honoraria, Research Funding. O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Holes:AbbVie Inc: Employment, Other: Stock/stock options. Jia:AbbVie: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Hutti:AbbVie: Employment, Other: Stock/stock options.

Introduction Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT) have a poor prognosis. Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that targets CD19, which is broadly expressed across B-cell malignancies, including DLBCL. Lenalidomide (LEN) is an immunomodulatory drug with antiproliferative and antiangiogenic effects. Combined tafasitamab + LEN has shown enhanced activity in in vitro and in vivo lymphoma models. L-MIND (NCT02399085) is an ongoing, open-label, single-arm, Phase II study of tafasitamab + LEN in patients with R/R DLBCL who are ineligible for ASCT. Here, we present results from prespecified patient subgroup analyses from L-MIND. Methods Patients aged ≥18 years with R/R DLBCL (1-3 prior systemic therapies, including ≥1 CD20-targeting regimen) with an Eastern Cooperative Oncology Group performance status 0-2, and who were ineligible for ASCT were enrolled. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during Cycles 1-3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4-12. LEN (25 mg orally) was administered on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint is objective response rate (ORR; partial response [PR] + complete response [CR]), assessed centrally by an independent review committee (IRC) per International Working Group criteria 2007, incorporating PET-based imaging. Secondary endpoints include ORR (investigator-assessed), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and biomarker analyses. Results Of 81 patients enrolled, 80 patients received tafasitamab + LEN and were included in the full analysis set (FAS) for efficacy (data cut-off 30 Nov 2018). Median follow-up was 17.3 months. In the FAS, ORR was 60.0% (95% confidence interval [CI]: 48.4-70.8) (Figure 1A). The CR rate was 42.5% (n=34/80), of which 88.2% (n=30/34) were PET-confirmed. Median time to response (PR or CR) was 2.0 months and median time to CR was 7.1 months. Median DOR was 21.7 months (95% CI: 21.7-not reached [NR]); median PFS was 12.1 months (95% CI: 5.7-NR); and median OS was NR (95% CI: 18.3-NR) with a median follow-up of 19.6 months. The 12-month DOR and OS rates were 71.6% (95% CI: 55.1-82.9) (Figure 1B) and 73.7% (95% CI: 62.2-82.2) (Figure 1C), respectively. In the subgroup analysis, patients with CR as best objective response (BOR) had better outcomes than those with PR: median DOR, NR (95% CI: 21.7-NR) vs 4.4 months (95% CI: 2.0-9.1); 12-month DOR rate, 93.2% (95% CI: 75.4-98.3) vs 14.4% (95% CI: 1.1-43.7); and 12-month OS rate, 97.1% vs 76.9%. Patients with one prior line of therapy had a trend for better outcomes than those with ≥2 prior lines: ORR, 70.0% vs 50.0%; and 12-month OS rate, 86.9% vs 60.1%. However, the 12-month DOR rate was similar regardless of the number of prior lines (one prior line: 70.5% [95% CI: 47.2-85.0] vs ≥2 prior lines: 72.7% [95% CI: 46.3-87.6]). For patients who were refractory to primary therapy or their last line of therapy, similar ORRs were observed to non-refractory patients (60.0% vs 60.0%); 12-month DOR was similar regardless of refractory status to last therapy; and 12-month OS rates were higher in non-refractory patients (Figure 1C). As expected, patients with a low/low-intermediate International Prognostic Index (IPI) score had better outcomes than those with an intermediate-high/high score: ORR, 70.0% vs 50.0%; 12-month DOR rate, 86.5% vs 50.4%; and 12-month OS rate, 87.0% vs 59.9%. Based on Hans algorithm, encouraging outcomes were reported in patients with germinal center B-cell (GCB) DLBCL (n=37), and outcomes were even better in those with non-GCB DLBCL (n=21): ORR, 48.6% vs 71.4%; median DOR, NR vs 21.7 months; 12-month DOR rate, 53.5% vs 83.1%; and 12-month OS rate, 65.4% vs 84.2%. Conclusions Tafasitamab + LEN combination followed by tafasitamab monotherapy shows encouraging activity with durable responses in ASCT-ineligible patients with R/R DLBCL. L-MIND includes a substantial number of poor prognosis patient subgroups. While the influence of these risk factors is evident, the clinical activity of tafasitamab + LEN in these difficult-to-treat patients is promising, particularly in those who were refractory to prior therapies. Disclosures Duell: Regeneron Pharmaceuticals, Inc.: Research Funding. Maddocks:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Merck: Research Funding; BMS: Research Funding. González-Barca:Janssen: Consultancy, Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Honoraria. Jurczak:TG Therapeutics: Research Funding; Roche: Research Funding; Takeda: Research Funding; Servier: Research Funding; Celtrion: Research Funding; Novo Nordisk: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: 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; Gilead: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding. Liberati:Incyte: Consultancy; Janssen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol & Mayer: Honoraria. de Vos:Bayer: Consultancy; Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Nagy:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. André:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Dreyling:Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Other: Scientific advisory board, Research Funding; Novartis: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Sandoz: Other: Scientific advisory board; Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau. Menne:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: 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; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Takeda: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: 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. Dirnberger-Hertweck:MorphoSys: Employment. Weirather:MorphoSys: Employment. Ambarkhane:MorphoSys: Employment. Salles:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria.

Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are a common indication for allogeneic hematopoietic stem cell transplant (HCT) in first complete remission (CR1). Despite HCT, relapses are common and cure rates are limited thereafter. The use of FLT3 inhibitors as post-HSCT maintenance therapy has not been prospectively evaluated in the phase 3 setting. Gilteritinib is a selective, potent FLT3 inhibitor with robust activity and favorable tolerability in relapsed/refractory AML. This trial will compare the safety and efficacy of 2-year maintenance therapy with gilteritinib versus placebo in patients with FLT3-ITD+ AML in CR1 after allogeneic HSCT. The broad goal of this study is to determine if there is a benefit to FLT3 inhibition as maintenance therapy post-HCT and to identify which patients, if any, benefit. We will use a novel NGS-based assay for FLT3-ITD mutations to detect minimal residual disease (MRD) in order to stratify patients pre-HSCT and correlate with relapse post-HCT. Study Design and Methods: This Phase 3, randomized, double-blind, placebo-controlled multicenter trial (NCT02997202; Blood and Marrow Transplant Clinical Trials Network Protocol 1506), is being conducted at 149 sites worldwide. The target enrollment is 532 adult subjects (aged ≥18 years) with FLT3-ITD+ AML in CR1 who are ≥30 days and ≤90 days from scheduled allogeneic HSCT. Of these 532 subjects, 346 subjects who have achieved successful engraftment without uncontrolled graft-versus-host disease (GVHD) or other serious toxicity will be randomized (1:1; stratified by conditioning regimen intensity, time from HSCT [Day 0] to randomization [30-60 days vs 61-90 days], and presence of minimal residual disease [MRD] in the pre-transplant bone marrow sample) to receive oral gilteritinib (120 mg) or matching placebo as maintenance therapy for 2 years. The primary endpoint is relapse-free survival (RFS) in the two treatment arms; RFS will be assessed from the time of randomization to the time of death or morphologic leukemia relapse (as defined by Revised IWG criteria). MRD status will continue to be monitored over the duration of the maintenance therapy, although investigators will be blinded to the MRD assay results. Overall survival is a key secondary endpoint. Other endpoints include safety/tolerability, non-relapse mortality, event-free survival, incidences of acute/chronic GVHD, and MRD. As of July 31, 2019, 341 patients have been registered and 236 have been randomized. To achieve a target number of 346 subjects for randomization (n=173 per treatment arm), we estimated that enrollment of 532 subjects would be required given an expected dropout rate of 35% between the time of registration to the time of randomization. The RFS rate in the placebo arm (control) is assumed to be 67% at 1 year, 59% at 2 years, and 55% at 3 years (according to the Center for International Blood & Marrow Transplant Research data for FLT3-ITD+ patients transplanted in CR1 who were alive and were progression free at 60 days). A total of 122 events will provide 85% power to detect a hazard ratio (HR) of 0.57 (corresponding to a 15% difference in 2-year RFS) with two-sided significance level of 0.05. With a 2-year accrual period and a 5% annual dropout rate, enrollment of 346 subjects will ensure a high probability of obtaining 122 events. The primary efficacy analysis will be performed using the intention-to-treat (ITT) population, which is defined as all subjects who are randomized. RFS will be compared across the treatment groups using the stratified Log-rank test. A stratified Cox model with treatment as covariate will be used to determine HR and confidence intervals at 1, 2, and 3 years. Kaplan-Meier estimates of RFS will be reported at 1, 2, and 3 years. No interim efficacy or futility analyses are planned. Figure Disclosures Levis: Daiichi Sankyo Inc: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Merck: Research Funding; Janssen: Consultancy. Rosales:Astellas: Employment. Delgado:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Horowitz:Actinium: Other: Unrestricted educational and research grant; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Janssen: Other: Unrestricted educational and research grant, Research Funding; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Chimerix: Other: Unrestricted educational and research grant; Regeneron: Other: Unrestricted educational and research grant. Chen:Incyte: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Takeda: Consultancy.

Introduction: Myelodysplastic syndrome (MDS) is characterized by differentiation blockade, cytopenias with commontransfusion dependency and immune defects. Upon progression the myeloblasts accumulate and the patients become vulnerable to severe infection complications. Based on the Prague Charles University General Hospital registry (N=164, median age 73), the AZA therapy in higher-risk MDS patients results in median OS 13.8 Mo with ORR 48.5%. We also noted from our retrospective data that AZA-treated patients with higher G-CSF consumption had significantly reduced occurrence of Grade 4 neutropenias and longer OS (19 vs 16 Mo, p value 0.039). Rationale: To improve poor clinical outcomes we initiated a randomized open labeled academic trial that compares standard AZA therapy (A) with novel AZA-based therapy combination involving use of G-CSF added prior AZA (GA). Both AZA and also decitabine were preclinically shown to induce myeloid differentiation upon G-CSF preincubation. G-CSF binds its receptor in granulocytic precursors and neutrophils to stimulate their survival, proliferation, and differentiation via myeloid master regulator transcription factor and leukemia-suppressor PU.1. We also have previously shown that AZA increases PU.1. expression. Study design & Methods: GA/MDS-2013 (EudraCT No 2013-001639-38). Expected for enrollment are 134 patients, currently enrolled 53 patients (GA arm N=29, A arm N=24) with median age 74 years, M:F ratio 32:21 (GA 16:16, A 13:8),median IPSS-R 6, median follow up 11.2 Mo, median cycles of therapy 6. Diagnosis included:MDS (EB1, EB 2) with IPSS int-2/high (75%), MDS/AML Results: The presented data include 2.5 years since the beginning of the trial. Median survival for GA arm was 11 vs 6 Mo in the A arm. ORR (CR, CRm, PR, HI) was 56% in GA arm vs 33% in the A arm. Transformation to AML for both arms was comparable. The stratified longitudinal Cox proportional hazards model containing time-varying covariates together with the ordinal multilevel logistic mixed model were utilized. From this joint fitted model, a negative coefficient for the G-AZA treatment (significant p-value 0.0442) can be noticed in the case of the Cox Proportional Hazard part of the model. This means that G-AZA treatment improves patient survival. The estimated odds for the GA arm that responded to the therapy with remission rather than progression is 12.4x higher than for the A arm, controlling for the remaining patients' characteristics (p-value 0.0016).Both the GA and A arms are comparably tolerated. Data on serious infections and neutropenia gr4 were not yet available. The levels of G-CSF in sera prior the study in both arms (GA vs A) were comparable. Flow cytometry revealed G-CSF mediated upregulation of FCgRI (CD64) in the GA but not in the A arm. Multivariate analysis indicates the following: mutated genes: DNMT3A (p-value 0.0157), EZH2 (p-value 0.0091), TP53 (borderline p-value 0.0510), & CSF3R (p-value 0.0057) shorten the overall survival. The significant negative effects on response was noted for mutated EZH2 (p-value 0.0208) and CSF3R (p-value 0.0424) genes. Conclusions: The current results supported by different methods and statistics indicates a beneficial effect of G-CSF pre-treatment to standard AZA therapy in higher risk MDS patients. G-CSF pre-treatment to AZA increases OS and ORR. In addition, we identified biomarkers that are negatively associated with patient survival and response including EZH2, DNMT3A, TP53, & CSF3R. Grant Support: Ministry of Health, #16-27790A. Institutional resources: Progres Q49 & Q26, UNCE/MED/016, LQ1604, SVV 260374/2017, RVO-64165. Disclosures No relevant conflicts of interest to declare.

Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Background: Despite unprecedented response rates associated with "novel agents", HDT/AHCT is a therapeutic mainstay for transplant eligible patients with MM. However, relapse is universal and almost all patients diagnosed with symptomatic myeloma will die of their disease. The immunosuppressive network orchestrated by regulatory myeloid or lymphoid cells and effector dysfunction characterize relapses in MM. We have shown that myeloma-infiltrating myeloid cells produce versican (VCAN), a large matrix proteoglycan that promotes tumor sustaining inflammation and immunosuppression. VCAN proteolysis by a-disintegrin-and-metalloproteinase-with-thrombospondin-motifs(ADAMTS) proteases generates versikine, a bioactive fragment ("matrikine") that regulates Batf3-dendritic cells that control CD8+-attracting chemokine networks. We have shown that VCAN proteolysis predicts post AHCT survival in myeloma in a small series of patients. Here, we explore whether VCAN proteolysis is prognostic of outcomes in an expanded cohort. Methods: Bone marrow core biopsies from patients who underwent HDT/AHCT for MM from 2015-2018 were analyzed at day 90-100 (n=66). ADAMTS protease-mediated VCAN proteolysis was analyzed by immunohistochemistry from the biopsies through detection of neo-epitope DPEAAE as described previously. CD8+ T cells per high power field (HPF) was calculated at 400X magnification (10X ocular with a 40X objective) for available patients (N=35). Patients were divided into low (1+), moderate (2+) and high (3+) groups based on the scoring intensity. Patient characteristics were compared between the three groups using chi-square test or ANOVA as appropriate. Correlation analyses for VCAN proteolysis and CD8+ T cells/HPF were performed using ANOVA and linear regression in patients with available data (n=35). Kaplan Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS). Multivariate analysis using Cox regression model were performed to correlate the association between VCAN proteolysis with PFS and OS using factors that affect outcomes: age, gender, cytogenetics, and treatment regimens. Logistic regression analyses were used to estimate predictors of 2-year OS and PFS. Data were analyzed using SPSS and p Results: A total of 66 patients were included and VCAN proteolysis intensity was observed as low (1+) in 32 (48.5%), moderate (2+) in 23 (35%) and high (3+) in 11 (17%) patients respectively. Baseline characteristics between the three groups were similar (Table 1). VCAN proteolysis did not correlate with pre-AHCT response rates but was associated with post AHCT response (>very good partial response, VGPR in low: 87.5%, moderate: 65%, high: 45.5%; p=0.016, Figure 1A). The median follow-up of survivors was 37 months (range 7-116). Higher VCAN proteolysis had worse median PFS (months) [9 (95% CI 0-24) in high vs. 29 (95% CI 11-47) in moderate vs. 53 (95% CI 43-63) in low; p=0.019, Fig 1B) but no difference was observed in OS (Figure 1C). On multivariate analysis, moderate/high VCAN proteolysis had significantly worse PFS compared to low cohort (HR 2.62, 95% CI 1.20-5.74; p=0.016), but not significant for OS (HR 1.82, 95% CI 0.78-4.20; p=0.164). High/moderate VCAN proteolysis was associated with worse 2-year PFS (OR 2.79, 95% CI 1.02-7.64; p=0.046) and 2-year OS (OR 4.26, 95% CI 1.32-13.74; p=0.015) respectively. VCAN proteolysis intensity also correlated with higher CD8+ T cells (median in low: 15.5, moderate: 26, high: 66; regression coefficient 21.9, 95% CI 11.8-32.0, p Conclusions: We demonstrate in an expanded cohort that VCAN proteolysis status is associated independently with post AHCT response status and PFS. Increasing VCAN proteolysis signal intensity was associated with progressively worse outcomes consistent with the hypothesis that VCAN proteolysis is a surrogate marker for an immunosuppressive environmental network that promotes MM survival and CD8 T cell dysfunction. VCAN accumulation and turnover maybe predictive of early risk of relapse and can form the basis of future clinical trials aimed at restoring anti-MM immunity guided by VCAN proteolysis status. Disclosures Dhakal: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

Introduction: CD19-specific chimeric antigen receptor (CAR) T-cell therapy is FDA approved in patients with relapsed or refractory large B-cell lymphomas. While 35-40% of patients may achieve a durable complete response (CR), the toxicity incurred with CAR-T therapy could impact the ability to receive subsequent treatment in those who progress after CAR-T infusion. Our prior data suggested that patients who experienced early progression had inferior overall survival. We now update our results and evaluate the impact of laboratory abnormalities and comorbidities at the time of progression on overall survival. Methods: Adults with large B-cell lymphomas who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included. Patients who received CAR T-cell therapy with additional concurrent protocol-specified therapy were excluded. Those who exhibited progressive disease (PD) or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined patients who progressed or received additional lymphoma directed therapy after last CAR-T cell infusion as early PD, with all other patients defined as late PD. We collected laboratory data closest to the date of progression. We defined an absolute neutrophil count < 1000, platelet count < 75K, Creatinine > upper limit of normal (ULN), INR > ULN, AST/ALT > 2.5x ULN, total bilirubin > ULN, and LDH > ULN as abnormal. Primary endpoint of this analysis was overall survival (OS) landmarked to date of progression. Secondary endpoints include sub-group analyses based on early PD as well as lab abnormalities at the time of progression. A multi-variate analysis with select baseline and progression variables was also performed. Results: We identified 66 patients who met the above criteria. Median follow up for the entire cohort is 30.4 months (range 0.1-64 months) by reverse KM method. Median time from last planned CAR infusion to progression was 43.5 days (range 11-658). Median OS of the entire cohort was 5.43 months (95% CI 3.75-12.2). 25 (38%) patients experienced early PD, which was associated with inferior OS (median 3.75 vs. 10.4 months, P=0.02). LDH > ULN at the time of progression defined a group with inferior outcomes (median OS 3.16 vs. 17.5 months, P1 indicator of hematologic and/or organ dysfunction (excluding LDH) at the time of progression had worse outcomes compared to those with one or fewer abnormalities (median OS 1.74 vs. 7.14 months, P=0.001). Multivariate analysis identified pre-CAR IPI score 4-5 (HR 6.33, 95% CI 1.97-20.36), LDH > ULN at progression (7.01, 95% CI 2.89-17.013), and abnormal creatinine at progression (5.32, 95% CI 1.71-16.53), as factors associated with increased risk of death. Conclusions: Patients with PD post CD19-specific CAR T-cell therapy, particularly those with early PD, elevated LDH, or renal failure experience extremely poor outcomes. These data can inform discussion of prognosis for patients who progress after CAR T-cell therapy and may predict which patients may benefit from additional anti-lymphoma therapy. Figure Disclosures Lynch: Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Juno Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding. Maloney:A2 Biotherapeutics: Honoraria, Other: Stock options ; Celgene,Kite Pharma: Honoraria, Research Funding; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria. Turtle:Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Ad hoc advisory board member; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Allogene: Other: Ad hoc advisory board member; Kite/Gilead: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member. Smith:Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Ignyta (spouse): Research Funding; Genentech: Research Funding; Denovo Biopharma: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Shadman:TG Therapeutic: Research Funding; Mustang Bio: Research Funding; Atara Biotherapeutics: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Research Funding; Verastem: Consultancy; Astra Zeneca: Consultancy; ADC Therapeutics: Consultancy; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Research Funding; Acerta Pharma: Research Funding. Ujjani:Pharmacyclics: Honoraria; Atara: Consultancy; Gilead: Consultancy; Genentech: Honoraria; Astrazeneca: Consultancy; AbbVie: Honoraria, Research Funding; PCYC: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding.

Background: Pyruvate kinase (PK) deficiency is an under-recognized hereditary disease that causes lifelong hemolytic anemia. Mutations in the PKLR gene lead to reduced red cell PK (PK-R) enzyme activity, resulting in defective glycolysis and decreased lifespan of red blood cells. Mitapivat (AG-348) is a novel, first-in-class, oral, small-molecule allosteric activator of PK-R under clinical testing as the first targeted, disease-altering therapy for PK deficiency. In the DRIVE PK study (NCT02476916; a phase 2, open-label, dose-ranging trial in adults with PK deficiency who are not regularly transfused), twice-daily (BID) dosing with mitapivat for >6 months was well tolerated and induced rapid, durable responses (Grace et al. ASH 2017). As of July 14, 2017, 26 (50%) of 52 enrolled subjects had a maximum hemoglobin (Hb) increase of >1 g/dL. Among these 26 subjects, the mean maximum Hb increase was 3.4 g/dL, and 25 (96%) had ≥1 missense PKLR mutation. Based on these findings, mitapivat has entered phase 3 clinical development. The design of the ongoing phase 3 ACTIVATE-T study and its extension study are reported here, with an update on country/site activation and key early learnings on trial logistics in PK deficiency. Methods: ACTIVATE-T is a global, multicenter, open-label study (NCT03559699) to evaluate the efficacy and safety of mitapivat in regularly transfused adults with PK deficiency. Regularly transfused is defined as ≥6 transfusion episodes in the previous year. Subjects who are homozygous for the R479H mutation or have 2 non-missense mutations (without the presence of another missense mutation) in PKLR will be excluded, as will subjects with an average transfusion frequency of more than once every 3 weeks in the previous year. The study comprises an 8-week screening period, during which each subject's complete transfusion history from the prior 52 weeks is documented, followed by a 16-week dose optimization period and a 24-week fixed-dose period (Figure). During the dose optimization period, each subject will undergo individualized mitapivat dose optimization. All subjects will start on a dose of 5 mg BID, which may be increased twice over the course of 16 weeks (from 5 to 20 mg BID and from 20 to 50 mg BID). In the fixed-dose period, each subject will receive mitapivat at their optimized dose for 24 weeks. During the study, subjects will be transfused when their Hb reaches or falls below their individual transfusion trigger calculated from their transfusion history. The primary endpoint is the proportion of subjects who achieve a reduction in transfusion burden, defined as a reduction of ≥33% in the number of red blood cell units transfused during the 24 weeks of the fixed-dose period compared with the historical transfusion burden standardized to 24 weeks. Secondary endpoints include safety. All subjects who complete the study will have the opportunity to enroll in an open-label extension study (NCT03853798) in which all participants will receive mitapivat for up to 192 weeks. The ACTIVATE-T trial is enrolling globally. Disclosures Lynch: Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mix:Agios: Employment, Equity Ownership. Porter:Bluebird bio: Consultancy, Honoraria; Silence therapeutics: Honoraria; Vifor: Honoraria; La Jolla: Honoraria; Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Agios: Consultancy, Honoraria.

Background The anti-PD1 antibody nivolumab is approved for relapsed or refractory classical Hodgkin lymphoma (cHL) showing high overall response rates (ORR) and a favorable safety profile. However, complete response (CR) is rare in this setting, and most patients develop progressive disease. To evaluate the efficacy of combined nivolumab and doxorubicin, vinblastine and dacarbazine (AVD) as 1st-line treatment for early-stage unfavorable cHL, we conducted the GHSG NIVAHL trial. Methods NIVAHL is a prospective, randomized, investigator-sponsored single-stage phase II trial that enrolled treatment-naïve early-stage unfavorable cHL patients between 18 and 60 years at 35 German centers (NCT03004833). In arm A, patients received 240mg nivolumab and AVD at standard doses on day 1 and 15 of each 28-day cycle for a total of four cycles (4xNivoAVD). In arm B, the same treatment was administered sequentially, starting with 4x nivolumab in 2-weekly intervals, followed by 2xNivoAVD and 2xAVD. Both groups received 30Gy involved-site radiotherapy (IS-RT). Primary endpoint is the centrally reviewed PET/CT-based CR rate after completion of protocol therapy including IS-RT. 55 patients per group were enrolled in order to exclude a CR rate ≤80% with a power of 90% on a one-sided alpha level of 2.5% each. Secondary endpoints will be analyzed descriptively and include treatment-related morbidity (TRMorbidity), progression-free (PFS), overall survival (OS), response at interim and final restaging as well as patient-reported outcomes. Sequential biopsies, blood and microbiome samples were collected for correlative studies. Results Between 04/2017 and 10/2018, a total of 110 patients were enrolled with one patient disqualified due to alteration of HL diagnosis by central pathology review (N=109, group A n=55, group B n=54). The median age of the predominantly female patients (60%) was 27 years. Stage II was present in 95% of cases with ≥3 involved areas as most common risk factor (69%), followed by elevated ESR (48%), large mediastinal mass (20%) and extranodal disease (13%). Mean duration of chemoimmunotherapy was 15 (standard deviation (SD) 3) weeks and 22 (SD 6) weeks with a mean relative dose intensity of 87.4 (SD 15.9)% and 85.8 (SD 24.2)% in groups A and B, respectively. Severe protocol deviations occurred in 4 patients in group A and 5 in group B. Reasons were toxicity (n=5), patient's wish (n=2), incorrect allocation to early-stage unfavorable risk group (n=1) and progressive disease (n=1). Another 2 patients refused to receive IS-RT. Any adverse events (AEs) were reported for 98% of patients. AEs ≥°3 were observed in 73% and 78%, respectively, and serious AEs occurred in 38% and 28% of patients in groups A and B, respectively. TRMorbidity defined as organ toxicity ≥°3 or anemia, thrombocytopenia or infection °4 was documented in 16% and 22% of patients; all of these were organ toxicities predominantly of liver and gastrointestinal tract, with 19/21 events occurring during the first 2 treatment cycles. Data on ongoing or late toxicities is limited by short follow-up. Until 07/2019, 4 cases of persistent hypothyroidism have been reported. At the 1st interim restaging after 2xNivoAVD and 4x nivolumab, the ORR was 100% (54/54) and 96% (49/51), with a CR rate of 85% and 53% in groups A and B, respectively. Interim remission status was not assessed in 1 and 3 patients, respectively, due to treatment discontinuation after incorrect allocation to early-stage unfavorable risk group (n=1) or toxicity (n=3). After completion of systemic therapy, ORR was 100% (54/54) and 98% (50/51) with a CR rate of 81% and 86%, respectively. One patient in group B developed histologically proven primary progressive HL during nivolumab monotherapy while no other case of progressive or relapsed disease or death has been documented so far. The centrally reviewed CR rate at the end of treatment will be reported at the meeting. Additionally, initial data from currently ongoing histopathologic and immunologic studies will also be presented. Conclusion Concomitant and sequential therapy with nivolumab and AVD is feasible with acceptable toxicity. In early-stage unfavorable cHL, concomitant Nivo-AVD induces a high early CR rate. The interim CR rate observed with 4x nivolumab monotherapy is higher than previously reported in relapsed or advanced-stage disease. The primary endpoint and initial PFS data will be reported at the meeting. Disclosures Bröckelmann: Bristol-Myers Squibb: Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Support, Research Funding; MSD Sharpe & Dohme: Research Funding. Kerkhoff:EUSA: Honoraria; Hexal: Honoraria; Celgene: Honoraria, Other: Travel Support; Roche: Honoraria; Novartis: Honoraria. Hüttmann:University Hospital Essen: Employment; Takeda: Honoraria; Gilead: Honoraria. Zimmermann:Takeda: Honoraria, Other: Travel Expenses; Novartis: Other: Travel Expenses; MSD: Other: Travel Expenses; BMS: Other: Travel Expenses. von Tresckow:MSD Sharpe & Dohme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria; Amgen: Honoraria. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Borchmann:Novartis: Honoraria, Research Funding. OffLabel Disclosure: Nivolumab 240mg i.v. 2-weekly for 1st-line treatment of classical Hodgkin lymphoma.

Background: GvHD-free, relapse-free survival (GRFS) is a useful composite endpoint that measures survival without relapse or significant morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to establish a predictive model of GRFS after allo-HSCT, using a machine learning algorithm within the Kyoto Stem Cell Transplantation Group (KSCTG), a multi-institutional joint research group of 17 transplantation centers in Japan. Methods: Consecutive patients with hematologic diseases who had undergone their first allo-HSCT between 1986 and 2016, were included in the study (n = 2,565). The primary endpoint was GRFS, and the secondary endpoints were: overall survival (OS), relapse, non-relapse mortality, and grades II-IV acute GvHD. Data were randomly split into the training set (70% of the dataset) and the validation set (30% of the dataset). The model was trained and tested using a 5-fold cross validation on the training set. A stacking ensemble of multiple machine learning algorithms was applied to develop a model. Predictions were first generated using different machine learning algorithms such as AdaBoost, Random Survival Forest, and Dynamic-DeepHit. A metamodel was subsequently trained using these predictions as inputs, to generate the final prediction (Figure 1). All models were trained using 28 input variables containing information on the patient and transplant characteristics. We used Cox Proportional-Hazards (Cox-PH) model as the benchmark case and evaluated the models' performance using the Harrell's Concordance Index (C-index). The model's final prediction can be directly used as a risk score for each patient. We validated this risk score in the validation set using the competing risk hazard model. Due to the small size of the validation set (N=770), we only classified the final risk scores into 2 groups as follows: high risk (above median) and low risk (below median) for each risk category. Results: The median age of the patients at transplantation was 48 years (range from 7 to 76). The sources of stem cells were related bone marrow (BM) in 650 patients, related peripheral blood (PB) in 382, unrelated BM in 978, unrelated PB in 24, and cord blood in 522. Myeloablative conditioning was administered in 1,293 patients and reduced-intensity conditioning in 949 patients. Refined disease risk indexes were low in 310 patients, intermediate in 1,197 patients, high in 545 patients, and very high in 368 patients. Median follow-up period of survivors was 4.5 years. For GRFS, our model achieved a higher C-index across all risk categories (C-index: 0.631) than other top-of-the-art competing risk models (Cox-PH: 0.620, Random Survival Forest: 0.627, Gradient Boosting: 0.609, Component-wise Gradient Boosting: 0.599, Dynamic DeepHit: 0.603). The model also showed the highest C-index for overall survival (C-index: 0.653), relapse (C-index: 0.703), non-relapse mortality (C-index: 0.636), and grades II-IV acute GvHD (C-index: 0.594). For GRFS, the probability after 1 year and 2 year was 24.9% and 15.2% for the high risk and 48.0% and 33.6% for the low risk, respectively (hazard ratio [HR] compared to the low risk: 1.88; 95% CI: 1.60-2.20) (Figure 2). The OS at 5 years was 43.4% for the high risk and 70.6% for the low risk (hazard ratio [HR] compared to the low risk: 2.41; 95% CI: 1.96-2.97). The cumulative incidence function (CIF) for non-relapse mortality at 5 years was 32.1% for the high risk and 21.4% for the low risk (HR 2.01; 95% CI: 1.38-2.91). The CIF for relapse at 5 years was 37.1% for the high risk and 16.4% for the low risk (HR 1.67; 95% CI: 1.25-2.23). Conclusions: A predictive model of GRFS after allo-HSCT was established, which could benefit physicians and patients during the clinical decision-making process. This also forms the basis for research on new prognostic biomarkers by evaluating their predictive power based on our model. Disclosures Kanda: MSD: Honoraria; Takeda: Honoraria; Bristol-Meyers Squib: Honoraria; Otsuka: Honoraria; Daiichi Sankyo Company: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Astellas: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria; JCR Pharmaceuticals: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392. Imada:Bristol-Meyer Squibb K.K.: Honoraria; Celgene K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria; Takeda Pharmaceutical Co.,LTD.: Honoraria; Novartis Pharma K.K.: Honoraria; Astellas Pharma Inc.: Honoraria. Takaori-Kondo:Takeda: Research Funding; Ono: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Kyowa Kirin: Research Funding; Chugai: Research Funding; Janssen: Honoraria; Pfizer: Honoraria.

Introduction: cGVHD exhibits both autoimmune and fibrotic features across multiple organ systems. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor that (1) decreases human T cell IL-21 and IL-17 secretion via STAT3, IRF4 and RORγt regulation; (2) increases percentages and function of Foxp3+ T regulatory cells via a STAT5-dependent mechanism; and (3) reverses established cGVHD in 2 distinct preclinical models. KD025 modulates the immune system by shifting the Th17/Treg balance towards homeostasis. Methods: KD025-208 enrolled 3 sequential cohorts (C) (C1: 200 mg QD, C2: 200 mg BID and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy. Treatment is in 28-Day continuous cycles until disease progression or unacceptable toxicity. The primary endpoint is the overall response rate (ORR) as per 2014 NIH response criteria in the mITT population. Additional endpoints include duration of response (DOR), corticosteroid (CS) dose reductions, failure free survival (FFS) and Lee Symptom Scale (LSS) score. Results: 17, 16 and 21 pts were enrolled in C1, C2, and C3 between Sep-2016 and Mar-2018. Data as of 8-Mar-2019 are included, reflecting a median duration of follow up of 112, 97 and 64 weeks (wks), respectively. At enrollment, median age was 52 yrs, median time from cGVHD diagnosis to treatment was 20 mos, and patients had received a median of 2 prior lines of therapy. 71% of patients were refractory to the last line of therapy prior to enrollment. 50% of pts had cGVHD in ≥4 organs. The median duration of treatment was 37, 33 and 39 wks, respectively. As of 30-Jun-2019, 24% of pts had received >18 months of KD025 therapy. 14 pts remain on KD025 treatment. Reasons for discontinuation included cGVHD progression (18), pt voluntary withdrawal (7), relapse of underlying disease (5), investigator decision (5), AE (3) and death (2). ORR (95% CI) was 65% (38%, 85%) in C1, 69% (41%, 89%) in C2, and 62% (38%, 82%) in C3, i.e. 65% (51%, 77%) across all 3 cohorts. Responses were achieved across key subgroups with ORRs of 62% (24/39) in pts with ≥2 prior lines of systemic therapy, 70% (19/27) in pts with ≥4 organs involved and 60% (25/42) in pts with severe cGVHD. CRs were observed in all affected organs except lung; PRs were observed in lung. Responses were rapid, and often achieved within 8 wks, although 4/35 responses occurred after 24 wks. Of note, organs with fibrotic manifestations such as lungs, joints and eyes responded after 24 weeks in some pts. Responses were durable, with a Kaplan-Meier (K-M) median DOR of 34 weeks across all cohorts. 57% of responders sustained a response for ≥20 wks. The K-M median DOR was 34 wks in pts with ≥2 prior lines of systemic therapy. FFS at 6, 12, 18 and 24 mos was 76%, 47%, 40% and 33%, respectively. Baseline median CS dose was 0.21 mg/kg/day of prednisone equivalent. During treatment with KD025, the median CS dose was reduced by 50%. 67% of pts reduced CS dose and 20% discontinued CS completely. The median CS dose reduction was 66% in responders and 25% in non-responders. 52% of pts reported a clinically meaningful improvement (≥7-point reduction) in LSS score during treatment with KD025 with a median time to improvement of 9 wks and a duration for responders of 21 wks. 63% of responders and 32% of non-responders reported a meaningful improvement in LSS score. KD025 was well tolerated with a median Relative Dose Intensity of 98%. Dose reductions/interruptions occurred in 21/54 pts; median duration of interruption was 8.5 days (range 3-20). AEs were consistent with those expected in cGVHD pts receiving CS. Common AEs were URI (35%), diarrhea (31%), nausea (31%), fatigue (30%), dyspnea (28%), increased LFTs (24%), and peripheral edema (22%). 63% had a Grade ≥3 AE; the most common was dyspnea (13%). Conclusions: Durable and clinically meaningful responses have been observed across all 3 cohorts. KD025 was well tolerated, allowing pts to remain on treatment and realize potential benefits of sustained therapy. Disclosures Jagasia: Kadmon: Consultancy; Incyte: Consultancy; Janssen: Research Funding. Salhotra:Celgene: Other: Research Support; Kadmon Corporation: Other: Non paid consultant. Bachier:Viracyte: Consultancy; Sanofi: Speakers Bureau; Kadmon Corporation, LLC: Consultancy. Lazaryan:Kadmon: Consultancy. Weisdorf:Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy; Incyte: Research Funding. Green:Kadmon Corporation, LLC: Employment. Schueller:Kadmon Corporation LLC: Employment. Huang:Kadmon Corporation, LLC: Employment. Yang:Kadmon Corporation: Employment. Eiznhamer:Kadmon Corporation: Employment. Aggarwal:Kadmon Corporation, LLC: Employment, Equity Ownership. Blazar:Fate Therapeutics, Inc.: Research Funding; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; RXi Pharmaceuticals: Research Funding; Alpine Immune Sciences, Inc.: Research Funding; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-Founder; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees. Lee:Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding.

Introduction: Systemic AL amyloidosis is a rare multisystem disease caused by an underlying plasma cell dyscrasia with amyloid fibril deposition causing progressive organ failure. Treatment of the underlying plasma cell disorder underpins the management of AL amyloidosis with bortezomib-based regimes as standard first line treatment. Thalidomide has activity in AL amyloidosis used in low doses in combination with cyclophosphamide and dexamethasone. Carfilzomib (Kyprolis), a second generation irreversible inhibitor of the proteasome, is licenced for treatment of relapsed refractory myeloma. This prospective phase 1 multicentre study was designed to define the maximum tolerated dose (MTD) and recommended dose (RD) of one weekly dose of carfilzomib in combination with a fixed dose of thalidomide and dexamethasone (KTD) in patients with relapsed refractory amyloidosis. Methods and Patients Patients were recruited for treatment with carfilzomib in escalating dose cohorts using a 3+3 dose escalation design at three planned dose levels (Table 1) - all participants received carfilzomib 20mg/m2 on cycle 1 day 1. The primary endpoint was to define the MTD, RD and assess the safety and tolerability of KTD. The key secondary endpoint was a preliminary assessment of the activity of KTD. Results A total of 10 patients were recruited (6 male, 4 female) with a median age of 64 years (30% >70 years). The mean time from AL amyloidosis diagnosis for Dose levels 0 and 1 was 7.8 years (SD ±3.87 yrs.) and 3.2 years (SD ± 1.80) respectively. All non-refractory patients had received at least two previous lines of therapy, with a maximum of four previous lines of therapy. The median creatinine was 77.0µmol/L, the median NT-proBNP was 53.3pmol/L and dFLC at the time of treatment was 77.0mg/L. Three evaluable patients were recruited to Dose Level 0 with no dose limiting toxicities (DLTs) observed. A further 3 evaluable patients were recruited to Dose Level 1 - one patient experienced a DLT (acute kidney injury). Hence, 3 further patients were recruited at this dose level. One participant had a serious adverse event (SAE) following day 1 dosing at 20mg/m2 - deemed not evaluable for DLT assessment as received no further treatment. Three further patients were recruited at Dose level 1 with no further DLT's. The data monitoring committee decided that it was not in the patients' best interest to proceed to Dose level 2, as significant evidence of activity at dose level 1 and concern about potential toxicity. As of June 2019, 7 participants have completed 3 cycles and 4 participants (40%) have completed 6 cycles. Responses were determined centrally according to amyloidosis consensus criteria 2005. The overall hematologic response rate at end of 3 cycles was 70%. This included: complete response - 1 (10%); very good partial response - 3 (30%) and partial response 3 (30%). Of the 3 participants at Dose level 1, 1 participant had a VGPR, 1 had PR and 1 had no response (discontinued at the end of cycle 2). One patient had no response by the end of cycle 2 (discontinued due to toxicity) and 2 patients with DLT's were not assessable for response. A total of 3 participants had SAE's: 1. At dose level 1, grade 3 acute kidney injury which was deemed to be DLT, which recovered with supportive care. 2. At dose level 1, pyrexia, hypotension and hypoxia requiring intensive care admission after day 1 dose of 20mg/m2. There was no clear evidence of infection and this was deemed to be a SAE due to carfilzomib (but not DLT). 3. At dose level 1, grade 3 abdominal pain deemed unrelated to study medication. There were 66 other grade 1 or 2 adverse events reported from 9 participants from the first 3 cycles. There were no SUSARs or deaths in the study reported to date. None of the patients had worsening cardiac function. Results here are preliminary with further endpoints and detail to be presented when all participants have completed therapy. Conclusion This study defined, in combination with thalidomide and dexamethasone, the recommended dose of carfilzomib was 45mg/m2 on days 1, 8 and 15. The MTD of carfilzomib was not reached. Three participants experienced a SAE and a number of participants had grade 1-2 AE's. At the end of 3 cycles, 70% of participants achieved a hematologic response with 40% VGPR or better which appears comparable to other studies in relapsed AL amyloidosis. KTD is a potentially effective regime that can be considered for further study in relapsed refractory systemic AL amyloidosis. Disclosures Garg: Novartis: Consultancy, Honoraria. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kishore:Celgene, Jazz, Takeda: Other: Travel expenses; Celgene, Takeda, Janssen: Honoraria, Speakers Bureau. Pitchford:Amgen: Other: Research funding to institution. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Oughton:Amgen: Other: Research funding to institution. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Wechalekar:Amgen: Research Funding; GSK: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria.