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Abstract Abstract 94 Background: Lymphoma diagnosed during pregnancy is a rare occurrence. Further, there is heterogeneity in clinical presentation and a range of lymphoma histologies resulting in a continued deficiency of lymphoma-specific data in the literature regarding prognosis, optimal therapy, maternal complications, and fetal outcome. Methods: A comprehensive retrospective analysis was completed for patients (pts) diagnosed (dx) with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) during pregnancy at 9 large U.S. academic centers over a 13-year period (1998–2011). The vast majority of cases were co-managed with high-risk maternal fetal medicine. Data on maternal disease characteristics, treatment details, obstetric complications, and fetal outcomes were analyzed. Results: 88 cases were identified with complete data available in 82. The median age of pts was 31 yrs (18–40). Lymphoma dx occurred at a median of 24 weeks (wks) gestation (5–40). 15% of pts were dx during the 1st trimester, 46% during the 2nd trimester, 35% during the 3rd trimester, while 4% (n=3) of pts had a pre-existing NHL dx (follicular lymphoma (FL)). 52% (n=43) of pts had NHL and 48% (n=39) HL. Of NHL cases, 83% (n=33) were B-cell and 17% (n=10) T-cell. B-cell histologies were DLBCL n=23 (including 2 primary CNS and 1 'double hit' NHL), FL n=5 (including 1 leukemic phase FL), Burkitt's lymphoma n=3, and mixed histology n=1; T-cell histologies were anaplastic large cell n=6, PTCL not otherwise specified n=2, and T-cell/NK NHL n=2. Pts with B-cell NHL and HL were dx at a median age of 29 yrs (range, 18–40), while T-cell NHL pts were dx at a median of 34 years (19–37). MRI without gadolinium was the most common imaging modality utilized for staging. 63% of NHL and 19% of HL pts had stage III/IV disease (25% of HL with stage IIB). Pregnancy was terminated in 6 pts (n=4 aggressive NHL and n=2 HD) to enable immediate chemotherapy (five in the 1st trimester [at 5, 8, 10, 10, and 12 wks] and 1 pt in the early 2nd trimester who required high-dose methotrexate). 48 pts (63%) initiated anti-lymphoma therapy at a median of 25 wks gestation (range, 13–37) with 79% of pts initiating therapy in the 2nd trimester (see Table 1). The median gestation at time of lymphoma dx for pts who received intra-partum treatment was 20 wks vs 34 wks for pts who had therapy deferred to post-delivery (p<0.0001). The overall response rate among pts who received therapy was 87% (74% complete remission). Notably, gestation went to full-term in 54% with delivery occurring at a median of 37 wks (31–40). Therapy was deferred until post-delivery in 28 pts (37%) and the majority of these pregnancies were also carried to term (median delivery at 38 wks). At a median follow-up of 41 months (6–157), the 3-year PFS and OS for all pts were 79% and 89% respectively. Histology-specific 3-year PFS and OS were: B-cell NHL: 73% and 82%, respectively; T-cell NHL: 50% and 90%, respectively; and HL: 90% and 95%, respectively (Figure 1). Detailed obstetrical information was available in 59 pts. There were minimal pre-term complications, the most common being induction of labor in 45%. Perinatal events included spontaneous rupture of membranes in 5% and pre-eclampsia in 8%. Further, there were no differences in these events detected among pts who received intra-partum treatment vs deferred therapy. No episodes of chorioamnionitis or endometritis were noted. There was 1 stillbirth that occurred at 19 wks gestation in a 34-year-old pt with double-hit NHL following 1 cycle of R-CHOP. The median birth weight of infants was 2427 grams (1005–5262) with no difference among pts who received intra-partum chemotherapy vs not (2637 grams vs 2212 grams, respectively; p=NS). Microcephaly was reported in 1 case following 4 intra-partum cycles of CHOP for DLBCL; there were otherwise no malformations detected. Conclusions: To our knowledge, this represents one of the largest experiences reported of lymphoma in pregnancy. Our data show that standard NHL and HL chemotherapeutic regimens (without anti-metabolites) administered during the 2nd and 3rd trimester, including as early as 13 wks gestation in select cases, is associated with minimal maternal complications or fetal detriment. In addition, pts with low risk clinical scenarios (e.g., indolent NHL and/or late gestational dx) had therapy safely deferred to post-partum. In our experience, this approach was associated with overall expected lymphoma-related survival. Disclosures: No relevant conflicts of interest to declare.

Abstract A device that would provide a rapid evaluation of hemostasis would greatly aid physicians in making scientific decisions regarding transfusion therapy; especially with perioperative bleeding. We performed a prospective in-vitro study with reconstituted, recalcified whole blood (n = 6) separated into samples containing specific deficiencies in platelets, plasma, lyophilized platelets and lyophilized plasma such that the concentrations of the specific platelet or plasma were 0%, 10%, 30%, 50%, and 100%. The whole blood was obtained from consenting healthy volunteers. Samples from the various concentrations of the reconstituted blood were subjected to the following point of care coagulation tests: activated clotting time (ACT), thromboelastogram (TEG), laboratory prothrombin time (PT), laboratory activated partial thromboplastin time (APTT) and Signature+ PT. ACT’s were performed for each of four celite doses (1.5 mg, 3.0 mg, 6.0 mg and 12 mg celite). The four dose celite ACT’s were performed in duplicate and the mean recorded. The TEG was performed in duplicate, and the mean was recorded. The signature+ PT was performed in duplicate, and the mean recorded. The laboratory PT, aPTT, Platelet Count and Fibrinogen were performed once each. ACT values were analyzed within each of the three preparations using analysis of variance. This assessed the strength of the relationship between blood constituent concentration and ACT, and determined whether this relationship differed across varying amounts of celite. Other coagulation parameters including TEG (mA), PT and APTT were analyzed using analysis of variance with a single term for blood constituent concentration. This model determined the strength of the relationship between these coagulation parameters and blood constituent concentration. In addition, the kaolin activated TEG and the signature+ PT was evaluated to determine the strength of the relationship between these tests and the variations in platelet and plasma concentrations. There was a significant correlation between the plasma, platelets and lyophilized plasma concentrations and ACT results (all p < 0.001). There was a significant correlation between plasma platelets and lyophilized plasma and the TEG MA and angle (all p < 0.028). There was a significant correlation between laboratory PT and APTT and plasma, platelets, and lyophilized plasma, lyophilized platelets (all p < 0.001). There was a significant correlation between the Signature+ PT and plasma, lyophilized platelets, and lypholized plasma and platelets (all p < 0.005), (figure 1). A better point of care coagulation device that is based on in-vitro additions of various therapies, and comparison of their effects on coagulation tests may provide better treatment of the bleeding patient. The Signature+ PT could provide the endpoint for such a device whereas the ACT was nonspecific and had a small change in results with large changes in plasma concentration. The additional benefit of lypholized plasma to behave similarly to human plasma may allow such a device to be built. Figure Figure

Abstract Abstract 2617 Introduction: ABT-348 is a potent, novel, adenosine triphospate competitive inhibitor of Aurora A, B and C kinases. ABT-348 is also a potent inhibitor of all members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase (RTK) families. ABT-348 has demonstrated strong antitumor activity in a variety of preclinical cancer cell line models, in vitro and in vivo, including leukemias as monotherapy and in combination with the DNA methyltransferase inhibitor, azacitidine. Objectives: The primary objectives of this study are to determine the safety and pharmacokinetics (PK) of orally and IV administered ABT-348 as monotherapy or in combination with azacitidine in patients (pts) with advanced hematologic malignancies. Secondary objectives include determination of the maximum tolerated dose (MTD) and exploration of biomarkers associated with ABT-348 activity. Methods: This phase 1 dose-escalation study of ABT-348 utilizes a modified continual reassessment method in pts with advanced hematologic malignancies: acute myelogenous leukemia (AML), acute lymphoblastic leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia and myelodysplasia (MDS). Adult pts with histological or cytological confirmed disease, ECOG status 0–2, adequate hematological, renal and hepatic function and without significant hypertension or proteinuria are eligible. This study has four arms consisting of ABT-348 administered on a 28-day (D) cycle. Pts receive ABT-348 monotherapy once daily (QD, Arm A) or twice daily (BID; Arm B) on Days (D) 1, 8, and 15 of a 28-day cycle under fasting conditions. In Arm C, ABT-348 is given on the same schedule as Arm A in combination with azacitidine (75 mg/m2) administered IV or SC on Days 1 – 7 of each 28-day cycle. In Arm D, pts receive ABT-348 monotherapy on the same schedule as Arm A, but via IV administration. Samples are collected for PK and biomarker analyses. Pts are treated until progressive disease (PD) or unacceptable toxicity. Adverse event (AE) severity is graded using NCI-CTCAE v4.0. Results: 39 pts (median age, 66 y [45–86]) have enrolled (Arm A, n=32; Arm B, n=4; Arm C, n=3). Of these pts, 27 had AML, 11 had MDS and 1 had CML. Pts received a median of 4 prior therapies (range, 1 – 8). Best response to last prior therapy was: complete or partial response in 3 pts, stable disease in 11 pts, PD in 24, and not determined in 1. Dose escalation is shown in the table. The first dose-limiting toxicity (DLT) of grade 3 pancreatitis was observed at 640 mg in Arm A. Due to this DLT, along with a second case of grade 3 pancreatitis, further enrollment in Arm A was held and Arms B and C were opened. A DLT of grade 4 acute kidney injury was seen at 440 mg in Arm C. ABT-348-related AEs in greater than 2 pts were proteinuria (23%), nausea (21%), diarrhea (18%), hypertension (13%), vomiting (10%) and fatigue (8%). Grade 3/4 ABT-348-related AEs were hypertension (13%), pancreatitis (5%), acute kidney injury (3%) and diarrhea (3%). One patient in Arm A achieved a CRi (640 mg). Five of 32 pts in Arm A were treated for ≥4 cycles, including 2 of 7 pts at ABT-348 doses ≥ 640 mg. Based on preliminary PK analyses, Cmax and AUC of ABT-348 were approximately dose proportional in the dose range studied (10–690 mg); co-administration of azacitidine had no apparent effect on ABT-348 PK. Evidence of dual aurora/VEGF receptor kinase inhibition has been demonstrated by induction of polyploidy and PlGF, respectively. 33 pts have discontinued and 6 remain on study. Conclusions: ABT-348 has demonstrated on-target biomarker and clinical activity in pts with advanced hematologic magnancies, and was well tolerated at doses below 640 mg in Arm A. PK appears to be dose-proportional. Dose escalation is ongoing in Arms B and C (with azacitidine); an IV formulation of ABT-348 will also be evaluated. Disclosures: Off Label Use: Clofarabine in AML. Tibes:Abbott: Research Funding. Chiu:Abbott: Employment, Owns stocks Other. Xiong:Abbott: Employment, own Abbott stock Other. Qin:Abbott: Employment. Ansell:Abbott: Employment, own Abbott stock Other. Albert:Abbott: Employment, own Abbott stock Other. Tse:Abbott: Employment, own Abbott stock Other. Oliver:Abbott: Employment, own Abbott stock Other. Sajwani:Abbott: Employment, own Abbott stocks and participated in study design, data collection, analysis, interpretation and reviewing approving study documents related to ABT-348 programs. Other. McKee:Abbott: Employment, own Abbott stocks Other. Ricker:Abbott: Employment, own Abbott stocks Other.

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin’s lymphoma (NHL) comprising 3 molecular subtypes: germinal center B-cell (GCB), activated B-cell (ABC) and class III. ABC patients (pts) have a poor prognosis. The immunomodulatory drug lenalidomide (Len) produces durable responses in pts with aggressive NHL (Witzig 2011), with preferential activity reported in non-GCB DLBCL (Hernandez-Ilizaliturri 2011). Methods: This randomized, multicenter, open-label, phase 2/3 study was conducted to determine the efficacy and safety of single-agent Len vs single-agent investigator’s choice (IC) in relapsed/refractory DLBCL pts who received ≥2 prior therapies, or were ineligible for stem cell transplantation or further combination chemotherapy. DLBCL subtype (GCB vs non-GCB) was determined by a central pathology lab using immunohistochemistry (IHC) per the Hans method (Hans 2004). Pts were stratified by subtype, then randomized 1:1 to receive Len (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin) until progressive disease (PD), unacceptable toxicity, or voluntary withdrawal. In the event of radiologically confirmed PD, pts in the IC arm were allowed to cross over to Len. The primary endpoint for Stage 1 was overall response rate (ORR), as determined by an Independent Response Assessment Committee. Progression-free survival (PFS), overall survival (OS) and subtype analysis using gene expression profiling (GEP) were exploratory endpoints. Concordance of GEP and IHC was evaluated from 3 separate laboratories. Results: IHC subtyping agreement rate among the 3 laboratories ranged from 87.5%-97.9%, and sensitivity of IHC to detect ABC or GCB subtypes vs GEP ranged from 92.3%-100.0%. By IHC, 102 DLBCL pts (GCB, n=48; non-GCB, n=54) were treated with ≥1 dose of Len or IC (modified intent-to-treat population) in Stage 1. In this heavily pretreated population, >90.0% of pts received ≥2 prior systemic chemotherapies; 25 pts in Len and 32 pts in IC received ≥3 prior systemic chemotherapy regimens. Median age was 65 y in the IC arm vs 69 y in the Len arm. Twenty-nine pts crossed over from IC to Len after confirmed PD. All pts, regardless of subtype or therapy group, experienced ≥1 treatment-emergent adverse event, with neutropenia, anemia, and thrombocytopenia being the most common. Efficacy data are presented in the Table. Pts with GCB or non-GCB DLBCL (per IHC) treated with Len had similar ORR, but the data suggested greater improvements in PFS and OS with Len vs IC in the non-GCB pts. In an exploratory analysis of pts subtyped by GEP, ABC pts treated with Len vs IC-treated showed greater improvements in ORR, PFS, and OS compared with GCB pts. Prespecified criterion to advance to Stage 2 was a 2-sided 15% significance level in ORR in favor of Len based on IHC-defined subtype. The data did not fulfill this requirement, and Stage 2 was not opened. Conclusion: Len monotherapy showed clinical activity in heavily pretreated pts with DLBCL. The data suggest improved ORR, PFS, and OS with Len vs IC in the non-GCB population as defined by IHC, and the difference appears to be more pronounced in the ABC population as defined by GEP. Subtyping by GEP is warranted in further studies of Len in DLBCL. Abstract 628. Table 1.Table. Efficacy DataBy IHCBy GEPOverallGCBNon-GCBGCBABCLen(n=51)IC(n=51)Len(n=23)IC(n=25)Len(n=28)IC(n=26)Len(n=14)IC(n=16)Len(n=11)IC(n=16)ORR, % (95% CI)27.5 (15.9-41.7)11.8 (4.4-23.9) 26.1 (10.2-48.4)12.0 (2.5-31.2)28.6 (13.2-48.7)11.5 (2.4-30.2)21.4 (4.7-50.8)12.5 (1.6-38.3)45.5 (16.7-76.6)18.8 (4.0-45.6)P Value .079 .279 .179 .642 .206PFS, med wk (95% CI)13.6 (8.6-17.7)7.9 (6.3-9.0) 10.1 (8.3-22.3)29.0 (6.3-20.6)15.1 (8.3-24.1)7.1 (5.3-8.4)13.2 (8.3-24.9)7.1 (6.0-20.6)82.0 (7.3-NA)6.2 (4.3-10.1)P Value .041 .550 .021 .506 .105HR (95% CI) 0.64 (0.41-0.99) 0.82 (0.43-1.57) 0.50 (0.27-0.92) 0.77 (0.35-1.68) 0.44 (0.15-1.23)OS, med wk (95% CI)31.0 (16.6-41.3)24.6 (12.7-33.9) 30.0 (14.9-44.4)24.9 (13.7-58.3)32.3 (15.9-48.1)20.4 (10.3-33.9)30.0 (18.0-34.6)20.1 (13.7-36.9)108.4 (9.6-108.4)18.6 (6.6-48.0)P Value .673 .526 .253 .767 .144HR (95% CI) 0.91 (0.59-1.41) 1.23 (0.65-2.34) 0.70 (0.38-1.30) 1.12 (0.52-2.42) 0.47 (0.17-1.33) Abbreviations: CI, confidence interval; HR, hazard ratio; med, median; NA, not applicable/not available. Disclosures Czuczman: Celgene: Consultancy. Off Label Use: This abstract describes a clinical trial of lenalidomide, which is an orally-available immunomodulatory agent under investigation for treating patients with diffuse large B-cell lymphoma.. Davies:GlaxoSmithKlein: Research Funding; Hoffman La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Gascoyne:Celgene: Consultancy, Research Funding. Salles:Pfizer: Honoraria; Gilead: Honoraria; Jansen: Honoraria; Hoffman La Roche: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Witzig:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zinzani:Mundipharma: Honoraria; Pfizer: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Millennium Takeda: Honoraria; Celgene: Honoraria; Teva: Membership on an entity's Board of Directors or advisory committees. Wright:Celgene: Research Funding. Staudt:Celgene Corporation: Research Funding. Repici:Celgene: Employment. Song:Celgene: Employment. Manzke:Celgene: Employment.

Abstract Abstract 1618 Introduction: Primary breast lymphoma is a rare type of non-Hodgkin lymphoma (NHL), representing about 1% of breast tumors and 2% of extranodal NHL. Diffuse large B-cell lymphoma (DLBCL) is the most common primary subtype presenting in the breast. Due to the low incidence of primary breast DLBCL, outcome data is limited. The aim of this study was to retrospectively assess the natural history of primary breast DLBCL in the pre and post rituximab eras, with specific emphasis on the incidence of local, systemic and central nervous system (CNS) relapses. Methods: Data was retrospectively collected on patients with primary breast DLBCL from seven USA academic medical centers. Institutional review board approval was obtained at each participating site. Patients were identified through institutional databases and tumor registries at each site. Charts were reviewed to obtain demographic and clinical variables including treatment history and dates of relapse and death when applicable. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. All histologies apart from primary DLBCL were excluded. Overall survival (OS) was calculated from the diagnosis date to the date of death or last follow-up. Time to Progression (TTP) was calculated from diagnosis data until the date of pathological evidence of recurrence or death. Data were summarized using descriptive statistics, and survival was analyzed using the Kaplan-Meier method. Results: Between 1984 and 2012, 75 patients were identified who met the eligibility criteria. The median age was 62 years (range 17–87); 81% presented with a palpable mass; 12% had their disease detected incidentally by mammography; 4% presented with B-symptoms; 59% had right breast involvement; 67% had stage I and 33% had stage II disease. The stage-adjusted international prognostic index (IPI) score was 0 in 28% of patients, 1 in 41%, 2, in 25%, 3 in 4% and 4 in 1%. 91% of patients were treated with chemotherapy; 31% of these were treated in the pre-rituximab era and 69% received rituximab. Radiation therapy (RT) was utilized in 68% of patients and was the only treatment modality in 8% of those receiving RT. 8% of patients received CNS prophylaxis with intrathecal chemotherapy. After a median follow-up of 4.5 years (range 0.6 – 20.6 years), the Kaplan-Meier estimated median TTP was 10.4 years (95% CI 6.2 – 14.6 years) and the median OS was 14.6 years (95% CI 6.5 – 22.6 years). The 5-year TTP and 5-year OS were 65% (95% CI 53–77%) and 75% (95% CI 64–86%) respectively. Among the patients who relapsed, 67% occurred within the first 2 years. A total of 7 relapses in the breast were observed, none in patients treated with combination of chemotherapy and RT. In univariate analysis, rituximab exposure was not associated with any difference in TTP or OS. The stage-adjusted IPI was associated with OS; the 5-year OS was 88% (95% CI 79–98%) in patients with a score of 0–1 versus 48% (95% CI 25–71%) in those with a score of 2–4 (log rank p < 0.001). The very limited-disease group with a stage-adjusted IPI of 0 had a 5-year OS of 94% (95% CI 83–100%) compared to all others who had a 5-year OS of 67% (95% CI 52–81%; log rank p = 0.001). There was no difference in TTP and OS in patients with solitary versus multiple breast masses or between patients with tumors less than versus more than 7cm. Patients receiving RT in addition to chemotherapy had a longer TTP than those who did not (log rank p = 0.03), but RT was not associated with an improved OS. Patients who relapsed and underwent stem cell transplant (SCT) had similar OS to those who never relapsed. Ten patients (13%) had CNS relapse (3 with leptomeningeal disease, 5 with brain parenchymal disease and 2 with both). All CNS relapses occurred within the first 2.8 years from the time of diagnosis. There was no difference in the rate of CNS relapse in the patients who received IT prophylaxis versus those who did not. Conclusions: In this multicenter study, the largest published to date, primary breast DLBCL appears to have a worse prognosis than early-stage DLBCL in nodal or other extranodal sites. RT was associated with improved TTP. Patients who relapsed were successfully salvaged with SCT, and had similar survival times to those who never relapsed. A high CNS relapse rate (∼1 in 8 patients, including parenchymal disease in 70%) was observed. The small numbers preclude definitive conclusions on the value of intrathecal prophylaxis or the utility of rituximab. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: I-131-CLR1404 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on initial preclinical and clinical experience and the exquisite radiosensitivity of MM, I-131-CLR1404 is being examined in RRMM in an open-label, dose escalation Phase 1 trial (NCT02278315) evaluating up to 5 cohorts and a maximum of 37.5 mCi/m2. Methods: The primary objective is to determine safety and tolerability of I-131-CLR1404 with and without dexamethasone (dex) in RRMM. Secondary objectives are to determine the recommended Phase 2 dose (RP2D) and therapeutic activity in RRMM. Eligibility criteria include progressive, relapsed/refractory MM, and at least one previous exposure to proteasome inhibitor (PI) and immunomodulatory (IMiD) drugs. Prior autologous stem cell transplant (ASCT) and external beam radiation therapy are allowed (≤ 20% of total marrow irradiated). There is no limit to the number of prior therapies. I-131-CLR1404 is administered intravenously as a single 30 minute infusion on day 1 with 40 mg dex orally weekly for 12 weeks. Dose-escalation uses a minimally modified, standard 3+3 schema with dose-limiting toxicities (DLTs) assessed through day 85 post-infusion. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the International Myeloma Working Group Uniform Response Criteria. Results: Ten patients have been enrolled in the study with data presented as of 30 Jun 2016 for 8 patients. Accrual is ongoing in the additional cohorts. Five patients were enrolled to cohort 1 (12.5 mCi/m2 + dex); 4 were evaluable and 1 patient was taken off study for rapid disease progression. Five patients have been enrolled to cohort 2 (18.75 mCi/m2 + dex), with data presented on 3 enrolled prior to data cutoff. The median age was 68.5 (range 55-85) and included 5 males and 3 females. All patients were standard risk (karyotyping) and median bone marrow plasma cell involvement was 25% (range 4-50%). Median number of prior therapies was 4 (range 2-12) (Table 1). Four of 8 patients previously underwent ASCT and 25% were previously treated with radiation therapy. Hematologic AEs (grade 3+) and non-hematologic AEs (grade 2+) potentially related to study drug are shown in Table 1. No difference in the toxicity profile was noted for patients with previous radiation therapy. Two serious adverse events (SAEs) have been reported, both in patients treated with 18.75 mCi/m2 I-131-CLR1404. One patient was hospitalized for a seizure (Day 62), assessed as unrelated to study drug and another patient was hospitalized for a grade 1 upper GI bleed in the setting of grade 4 thrombocytopenia (Day 23). This is believed to be the result of rapidly progressive disease, however relationship to I-131-CLR1404 could not be ruled out. Stable disease was achieved in 100% of evaluable patients (n=7). One subject in cohort 1 demonstrated a > 30% reduction in serum m-protein. Figure 1 provides a summary of percent change in serum free light chain assay (FLC) from baseline. Three patients had a reduction in FLC > 50%, 2 in cohort 1 and 1, to date, in cohort 2. Three patients had a stable FLC response through at least 22 days following treatment and 1 subject was unresponsive with regard to FLC. Median follow-up is 6.8 months (range 1.2-14.2). Patients did not receive subsequent systemic therapy for a median of 3.5 months (range 0.6-4.7). Furthermore, 1 subject in cohort 2 maintains stable disease and has not initiated subsequent treatment. Median progression free survival (PFS) is 3 months and included 4 patients with stable disease at the end of the 85 day study follow-up. In patients with progression after I-131-CLR1404, treatment included daratumumab (n=4), ASCT (n=1), and bortezomib, lenalidomide, and dex (VRD) (n=1). Conclusions: I-131-CLR1404 represents a unique, first in class targeted radiotherapeutic for MM. Preliminary data from this trial show an acceptable and expected safety profile with an efficacy signal in the initial 2 of a potential 5 cohorts. All evaluable patients, despite extensive previous therapy and refractoriness to new therapies, achieved disease stabilization. The study is ongoing to determine the RP2D and long term efficacy. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Oliver:Cellectar Biosciences: Employment.

Background Primary leiomyoma is a rare cause of a mass in the hand, with few reported cases to date. To our knowledge, this constitutes the most comprehensive and up-to-date systematic review of the literature of all cases of primary hand leiomyoma. We also provide an additional case recently managed in our practice of confirmed primary vascular leiomyoma of the hand in a 44-year-old woman to add to the current body of literature. Methods We performed a comprehensive literature review of all articles published on primary leiomyoma of the hand. The PubMed database was used, with search terms leiomyoma hand, angioleiomyoma hand, and angiomyoma hand. Articles were selected for their accuracy in anatomic localization in the hand and confirmed pathology of leiomyoma. Results Our initial search query resulted in 216 articles. After applying the inclusion criteria, we identified 50 individual articles with 108 cases of confirmed primary leiomyoma in the hand from January 1, 1954, to July 1, 2018. Common initial clinical impressions recorded for primary hand leiomyoma included ganglion cyst, giant-cell tumor, hemangioma, and glomus tumor. Patients presenting with leiomyoma of the hand frequently describe a painful lesion, which differs from most other benign tumors of the hand at presentation. Conclusions Leiomyoma is an important consideration when developing a differential diagnosis for primary benign masses in the hand. We hope that this comprehensive review can provide increased awareness of this tumor type.

Abstract Background: Follicular lymphoma (FL) is the second most common nodal lymphoma worldwide and remains incurable for most patients (pts). FL is recognized to be a highly heterogeneous disease and a subset of pts experience remarkable poor outcome. In a recent study, 19-26% of pts receiving first-line R-CHOP experienced progression of disease (POD) within 24 months after diagnosis and had a 5-year (yr) overall survival (OS) of only 34-50%, as compared to a 5-yr OS of 90-94% for pts without POD within 24 months (Casulo et al., J Clin Oncol 2015). Consequently, event-free survival at 12 (EFS12) and 24 months (EFS24) have been suggested as novel surrogate endpoints for poor overall survival in clinical trials and useful for patient counseling (Maurer et al., ASH 2014). We have previously shown that a clinicogenetic risk model (m7-FLIPI) that includes the mutation status of seven genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), the FL International Prognostic Index (FLIPI), and the Eastern Cooperative Oncology Group (ECOG) performance status, improves risk stratification for failure-free survival (FFS) and OS in pts with FL receiving first-line immunochemotherapy (Pastore et al., Lancet Oncology 2015). An online tool is available at: http://www.glsg.de/m7-flipi. It would be advantageous to determine prognosis prior to front-line therapy rather than after POD. Thus, we aimed to investigate the predictive utility of the m7-FLIPI for early POD. Patients and Methods: Clinical and mutation data were available from two independent cohorts: 151 pts who received R-CHOP and IFN maintenance as part of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG), and 107 pts from a population-based registry of the British Columbia Cancer Agency (BCCA) who received R-CVP. Among the latter, 93 (87%) received R-maintenance by intention to treat. All pts had symptomatic, advanced stage or bulky disease considered ineligible for curative radiotherapy, and a biopsy specimen obtained </=12 months prior to the initiation of first-line therapy. POD was defined as progression, relapse, or death due to any cause. POD12 and POD24 were defined based on POD status at 12 and 24 months after therapy initiation, respectively. Logistic regression analysis was performed to assess if m7-FLIPI was predictive of early POD using the statistical software R (version 3.1.2). Results: In the GLSG cohort, median age was 57 yrs (range 27-77), 51% had high-risk FLIPI, and 5-yr failure-free survival (FFS) and OS rates were 66% and 83%, respectively (median follow-up for OS 7.7 yrs). In the BCCA cohort, median age was higher (62 yrs, 37-83), but high-risk FLIPI was similarly frequent (50%); 5-yr FFS and OS rates were 58% and 74%, respectively (median follow-up for OS 6.7 yrs). A total of 43 GLSG (28%) and 24 BCCA pts (22%) were classified as high-risk by m7-FLIPI, with a 5-yr OS of 65% and 42%, respectively. In the GLSG cohort, 8 (5%) and 29 pts (19%) had POD within 12 and 24 months, respectively, 4 and 10 pts were censored before POD12 and POD24 (table). High-risk m7-FLIPI pts were significantly more likely to experience early POD with an Odds Ratio (OR) of 20.80 (95% confidence interval (CI) 3.53-395.96; p=0.0052) for POD12 and 6.33 (95% CI 2.67-15.69; p<0.0001) for POD24. Likewise, in the BCCA cohort, 16 (15%) and 28 pts (26%) experienced POD12 and POD24, respectively (table). The OR for high-risk m7-FLIPI pts was 4.69 (95% CI 1.52-14.65; p=0.0068) for POD12, and 5.36 (95% CI 2.03-14.60; p=0.0008) for POD24. In the GLSG and BCCA cohorts, the m7-FLIPI had a sensitivity of 88% and 50%, a specificity of 75% and 82%, a positive predictive value (PPV) of 16 and 33%, and a negative predictive value (NPV) of 96% and 90% to predict POD12. For POD24, sensitivity was 62% and 46%, specificity 79% and 86%, PPV 42% and 54%, and NPV 82% and 82%, respectively. Conclusion: We conclude that patients classified as high-risk m7-FLIPI are highly enriched among those with early progression of disease. However, approximately one-half of patients with progression by 24 months after therapy initiation are classified as low-risk m7-FLIPI. Thus, further efforts are needed to refine the m7-FLIPI and thereby capture additional cases that may benefit from innovative first-line approaches. Table. Population m7-FLIPI N POD12 POD24 GLSG Total 151 8/147* 29/141* High-risk 43 7 18 Low-risk 108 1 11 BCCA Total 107 16/107 28/107 High-risk 24 8 13 Low-risk 83 8 15 *Pts censored were removed Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Abstract Abstract 677 Background: Activating mutations of NRAS and KRAS (‘RAS’) are found in 10–30% of myeloid malignancies. Evidence of constitutive activation of the RAS-RAF-MEK-ERK pathway, however, is more ubiquitous. Trametinib is a potent, selective, allosteric inhibitor of MEK1/2 that inhibits proliferation of myeloid cell lines in vitro. A Phase I/II study of single, daily, oral dosing of trametinib in myeloid malignancies is ongoing. Here we report the results from Phase I/II patients receiving the recommended Phase II dose (RP2D) of 2 mg. Methods: Patient eligibility was limited to patients with relapsed/refractory myeloid malignancies and adequate hepatic, renal and cardiac function. There were no hematologic eligibility criteria. Patients were prospectively screened for KRAS mutations at amino acids 12, 13 and for NRAS mutations at amino acids 12, 13 and 61. Clinical response was assessed using International Working Group (2003 and 2006) criteria for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), respectively. Pharmacodynamic marker (pERK) analysis was conducted in phase II patients with patient paired (pre/during treatment) blood and bone marrow samples. Results: Eighty-seven (9 in Phase I and 78 in Phase II) patients received 2 mg of trametinib daily: AML (n=66), MDS (n=11), chronic myelomonocytic leukemia (CMML) (n=7) or other (n=3) (RAS mutations, n=57; RAS wild type, n=15 and RAS unknown, n=15). Median age was 68 years (range 21–87) and for close to half of the patients, trametinib was 3 3rd line of therapy. Trametinib exhibited a long effective half-life with small peak/trough ratios, and the exposure profile maintained time above preclinical target threshold for the 24-hour dosing period. Results of the pharmacodynamic analysis indicated an on-target effect of trametinib. Responses by RAS mutation status for Phase I/II subjects are summarized in Table 1. Responding patients have continued therapy for median of 16.9 weeks (range, 10.9 – 36.7). Drug-related grade 3/4 adverse events (AEs) were encountered in 31/87 (36%) of the Phase I/II patients and there was one grade 5 drug-related AE,cerebrovascular accident. Hepatic toxicities (9%), gastrointestinal disorders (7%) and rash (5%) were the most frequent grade 3/4 AEs. AEs possibly related to inhibition of MEK signaling were blurred vision (total,13%; grade 3, 1%) and decreased cardiac ejection fraction (total, 9%; grade 3, 6%); events were generally reversible. Conclusion: At the RP2D of trametinib (2 mg orally daily), trametinib has shown promising clinical activity and responses (CR/CRp/Marrow CR/MLFS/PR) were almost exclusively seen in patients with refractory myeloid malignancies characterized by somatic RAS mutations. Expansion of the CMML cohort for RAS positive subjects is ongoing. Disclosures: Borthakur: GlaxoSmithKline, Sigma-Tau, Eisai, XBiotech: Research Funding. Off Label Use: Trametinib, to report outcome of clinicla trial to audience at ASH meeting. Foran:GlaxoSmithKline: Research Funding. Platzbecker:GlaxoSmithKline: Honoraria, Research Funding. Giagounidis:GlaxoSmithKline: Honoraria. Ottmann:GlaxoSmithKline: Clinical trial participation Other. Kadia:GlaxoSmithKline: Research Funding. Bauman:GlaxoSmithKline: Employment, Equity Ownership. Wu:GlaxoSmithKline: Employment. Liu:GlaxoSmithKline: Employment. Schramek:GlaxoSmithKline: Employment. Zhu:GlaxoSmithKline: Employment. Wissel:GlaxoSmithKline: Employment, Equity Ownership.

INTRODUCTION: An unmet need exists to find effective therapy in more severe ulcerative colitis (UC) patients, especially those who have failed multiple therapies. The efficacy and safety of upadacitinib, a selective Janus Kinase 1 inhibitor, has been assessed in an 8-week double-blind, placebo-controlled, dose-ranging, phase 2b induction study in adult patients with moderately-to-severely active UC (U-ACHIEVE). 1,2 METHODS: In U-ACHIEVE, adult patients with moderately-to-severely active UC as determined by the Adapted Mayo Score (5-9 points and centrally-read endoscopy subscore 2-3) were randomized to receive extended-release upadacitinib 7.5, 15, 30, 45 mg once daily (QD) or placebo for 8 weeks. In the current sub-analysis, the efficacy of upadacitinib in more severe and/or more refractory patient populations was assessed. Patients who at baseline had failed ≥2 prior biologic agents, had pancolitis, and/or an Adapted Mayo score >7, were included. Pairwise comparisons between upadacitinib doses and placebo for the primary endpoint, clinical remission per Adapted Mayo Score at Week 8 (defined as stool frequency subscore ≤1, rectal bleeding subscore = 0, and endoscopic subscore ≤1) and secondary endpoints were conducted using the Fisher's Exact test and no multiplicity adjustments were applied. Non-responder imputation was utilized for missing values. RESULTS: At baseline, 142 (56.8% of the total study population) patients had failed ≥2 prior biologics, 135 (54.0%) patients had pancolitis, and 90 (36.0%) patients had an Adapted Mayo score >7. The proportions of patients achieving endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were significantly higher (nominal P -value < 0.05) with upadacitinib doses ≥30 mg QD versus the placebo group in patients who failed ≥2 biologics or had pancolitis at baseline (Table 1). Trends of higher proportions of patients achieving clinical remission per Adapted Mayo score, endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were observed with all upadacitinib groups versus placebo in all the sub-analyses. CONCLUSION: In this dose-ranging induction study, upadacitinib demonstrated greater efficacy compared to placebo with dose response in the more severe and refractory population; significantly greater efficacy was demonstrated with upadacitinib at doses ≥30 mg QD for most of the endpoints evaluated.