Go, Ronald S.

Abstract Background: Prolymphocytic leukemia (PLL) is a rare cancer with incidence of 0.48/1,000,000. It is comprised of 2 subtypes, T or B cell. It generally is associated with a poor median OS of 1-3 years. However, some patients have an initial smoldering course not requiring treatment. Limited population data exists describing the outcomes of PLL. We studied PLL patients who met a definition of smoldering, not requiring treatment within 180 days of diagnosis, using the National Cancer Data Base (NCDB). Methods: Patient level data were obtained from the NCDB Participant User File. The NCDB collects hospital cancer registry data representing 70% of newly diagnosed cancer cases in the US population. We identified PLL patients (ICD-O: 9832 PLL, NOS, ICD-O: 9833 B-PLL, and ICD-O: 9834 T-PLL) diagnosed in 2004-2015 for demographics, disease and treatment characteristics. We included patients diagnosed from 2004-2013 in the overall survival (OS) analyses. Patients who received no treatment as part of their first course of treatment and who did not have a subsequent treatment within 180 days were considered smoldering PLL. Results: From 2004-2015, 1606 patients were diagnosed with PLL and 451(28%) were smoldering PLL. Of the 1606 patients, T-PLL represented 781(49%), B-PLL 480(30%), and PLL, NOS 345(21%). Of the 451 smoldering PLL patients observed as T-PLL represented 48%(215), B-PLL 29%(133), and PLL, NOS 23%(103). The median age at diagnosis was 69 [59 - 78] years. There was a male predominance with 60 % males. The median OS for the entire cohort was 20.6 months. The % 5yr overall survival (OS) for smoldering PLL was 40% vs 29%(for non-smoldering). Within the PLL subtypes PLL, NOS and B-PLL were associated with better 5yr OS 38.56% and 35.53%, compared to T-PLL 12.89%. Only 65(4%) patients underwent an early stem cell transplant(SCT). Conclusions: We identified a population of patients not needing treatment within 180 days of diagnosis representing smoldering PLL with a significantly improved OS. Additionally, PLL, NOS and B-PLL were associated with an improved OS. The use of early SCT is low in PLL. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Langerhans cell sarcoma (LCS) is a rare malignant neoplasm of Langerhans cells characterized by multi-organ involvement and an aggressive clinical course.Given the rarity of the disease, the true epidemiological data on LCS are lacking, and most of our knowledge is obtained from institutional case series. In this study, we utilized two national databases- the Surveillance, Epidemiology, and End Results (SEER) Program database (https://seer.cancer.gov/) and National Cancer Data Base (NCDB) to study the incidence, clinical presentation, and outcomes of LCS. Methods: We calculated LCS incidence (cases/10, 000, 000 individuals) from SEER database using SEER*Stat (v 8.3.4; https://seer.cancer.gov/seerstat/) statistical software. SEER is a population-based registry program of the United States National Cancer Institute that covers approximately 28% of the population. We identified LCS cases that were confirmed histologically using International Classification of Diseases for Oncology edition 3 (ICD-0-3) histology code 9756/3 from SEER 18 (2000-2014) registry. As the disease was mandatory reportable only after 2001, we included cases that were diagnosed after 2001 in the analysis. Demographic patterns, clinical presentation, and overall survival (OS) were calculated utilizing the patient level data from the NCDB Participant User File. NCDB is a joint program by the American College of Surgeons and American Cancer Society that represents approximately 70% of newly diagnosed cancer cases in the nation. All patients aged > 18 years with a diagnosis LCS (ICD-0-3 Code 9756/3) from 2004 to 2015 were included. To ensure accuracy of follow-up, we excluded the patients that were not treated at the same facility of diagnosis from survival analysis. Results: A total of 25 cases of LCS were reported to SEER between 2000 and 2014. The overall incidence of the disease was 0.2 per 10,000,000 [95% CI:0.1-0.3] and was similar among males and females (p=0.33). The incidence of the disease did not differ significantly among different races (whites, blacks and other races) (p=0.56). Between 2004 and 2015, 52 patients with newly diagnosed LCS were identified from NCDB and 60% were males. The median age of diagnosis was 62 (range, 19-90 years). The most common sites of the presentation were connective tissue (29%; n=15), reticuloendothelial system (RES) and hematopoietic system (25%; n=13), skin (19%, n=10), gastrointestinal (10%, n=5), bones and joints (8%, n=4), brain (2%, n=1) and breast (2%, n=1). Site specific details were missing in 27% (n=14) of cases. Out of the 52 patients, twenty patients (39%) received chemotherapy as first-line therapy, while 24 (46%) received surgery and 15 (29%) received radiation therapy. After a median follow up of 18 (range, 1-144) months, 27 patients (52%) had died. The one- year survival rate was 62%, and the median OS was 19 months (Fig. 1A). We also calculated the 1-year disease-specific survival and OS using SEER database, and was 74% and 63%, respectively. After censoring the patients with hematopoietic and RES involvement, the patients who were managed with radiation therapy (median dose 3960 cGy, range 750-6400) had a better OS as compared to those who received no radiation therapy (p=0.03, Fig. 1B). On the contrary, after excluding the patients with hematopoietic and RES as primary site, no significant difference in OS was noted between the patients who were managed with and without surgery (17 vs 21 months; p = 0.75; Fig. 1C). In addition, post-surgical radiation or chemotherapy had no significant benefit in median OS (p=0.25). Among patients with hematopoietic and RES involvement, there was no association between OS and receipt of chemotherapy (p = 0.16; Fig. 1D); however, the number of patients who received chemotherapy was small (n=6). Conclusion: This dual-national registry study shows that LCS is extremely rare, and has a poor prognosis. Although the data regarding optimal management of LCS are limited, our study demonstrates that radiation therapy may offer survival advantage in patients without hematopoietic and RES involvement. Disclosures No relevant conflicts of interest to declare.

Abstract Background: We previously reported successful treatment of myeloma with an oncolytic virus, MMV-NIS. Preexisting immunity against measles made use of that virus unsatisfactory. The Indiana strain of Vesicular Stomatitis Viruses (VSV) are being developed as anticancer drugs for the treatment of a variety of malignancies. To ensure tumor selective replication and spread, we designed the VSV to encode interferon beta. Expression of IFNβ also serves as a STING agonist to activate host immunity against the cancer. The sodium iodide symporter (NIS) is inserted as a reporter gene into the viral genome to enable noninvasive monitoring of viral spread using PET/CT imaging. We report a Phase I clinical trial of intravenous administration of VSV-IFNβ-NIS for relapsed hematological malignancies including MM, AML, and TCL. Methods: Arm A consisted of patients with low tumor burden. Arm B included patients with high tumor burden. Both arms consisted of a classical 3+3 phase I trial, starting at 5x10^9 TCID50 (dose level 1) through 5x10^11 TCID50 (dose level 4), given as a single IV dose. In order to obviate potential toxicity from high interferon levels, Arm B received ruxolitinib 15 mg twice daily for 10 days beginning on day -1. The primary objective was determining the maximum tolerated dose (MTD) of VSV-IFNβ-NIS alone and in combination with ruxolitinib; secondary objectives include estimating the safety profile and preliminary efficacy. Correlative objectives include monitoring the pharmacodynamics of viral replication through SPECT/CT imaging with NIS gene, viremia, virus shedding, changes in the immune profile of peripheral blood leukocytes, and immunohistochemistry for immune cell infiltrates in tumors. Adverse events (AEs) are reported herein based on CTCAE v4 with the exception of cytokine release syndrome (CRS) which is based on Lee (Blood 2014; 124(2):188-195) criteria. Results: To date, 10 patients have received IV VSV-IFNβ-NIS; 8 in Arm A and 2 in Arm B. In Arm A, 3 patients were treated at dose level 1, 3 at dose level 2 and 2 at dose level 3. At dose level 1, there were three grade 3 hematologic AEs (neutropenia [1], lymphopenia [2]), and no grade 3+ non-hematologic AEs. At dose level 2, there were two grade 3 hematologic AEs (anemia [1], lymphopenia [1]), and two grade 3 non-hematologic AEs (nausea [1], dehydration [1]). A grade 2 CRS by Lee criteria was also observed. At dose level 3, 2 patients have been enrolled and data are maturing for DLT evaluation. In Arm B (VSV + rux), 2 patients have been enrolled and data are maturing for dose limiting toxicity (DLT) evaluation. Other grade 1 and 2 toxicities have included fever, hypertension, headache, electrolyte abnormalities, nausea, vomiting, transient elevation of liver function tests and creatinine. All grade 1 and 2 toxicities resolved within 72 hours. Among the 6 patients evaluable for response, there was one partial remission (TCL patient treated at dose level 2), and 5 with progressive disease. Multiple cytokines increased at 4h post infusion of virus, but most returned to baseline levels by 24h.Viremia was detectable in all patients at the end of infusion, and to varying levels at 30 mins, 1, 2, 4, 24, 48h or 72 hours post virus infusion. No persistent viremia was observed. No infectious virus was recovered in buccal swabs or urine and neutralizing anti-VSV antibodies were present by day 29. Extensive immune phenotyping and ELIspot assays for shared antigens are ongoing. Conclusion: In the lowest dose levels tested to date, VSV-IFNβ-NIS has not led to any observed dose limiting toxicity. Dose escalation is ongoing and updated results will be reported. Disclosures Lacy: Celgene: Research Funding. Peng:Vyriad: Equity Ownership. Russell:Vyriad: Equity Ownership. Dueck:Bayer: Employment; Phytogine: Employment; Pfizer: Honoraria. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:spectrum: Consultancy, Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; Medscape: Consultancy; celgene: Consultancy; Apellis: Consultancy; Prothena: Honoraria; Amgen: Consultancy; annexon: Consultancy; Abbvie: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; Alnylam: Honoraria. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Al-Kali:Novartis: Research Funding. Naik:Vyriad: Equity Ownership. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background Thrombotic microangiopathy (TMA) is a clinicopathologic diagnosis that can be characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and end-organ damage. Though most patients will present with the hematologic abnormalities of MAHA and thrombocytopenia, there are some that never demonstrate those features and only present with acute renal injury. Here we describe the clinical presentation, laboratory assessment, management, and outcomes of patients with renal-limited TMA (rTMA). Methods After IRB approval, the electronic medical record was searched from 2008-March 2017 for patients managed at our institution with a clinical diagnosis of rTMA supported by renal biopsy. Inclusion criteria were as follows: 1) Presence of TMA on renal biopsy, 2) Absence of MAHA 3) No history of renal transplant prior to diagnosis of TMA. Clinical notes were reviewed to document the physician-determined cause of TMA. If no cause was listed, cause of TMA was based off of labs and clinical observation. Results Thirty-five patients (18 female) met clinical criteria for a diagnosis of rTMA. Median age at time of biopsy was 59 years (range 9 to 87). Creatinine at time of biopsy was 2.4 mg/dL (range 0.55 to 6.4). Evidence of chronic TMA was noted on 17 specimens and an additional 3 had findings of chronic and acute TMA. Ten patients had ADAMTS13 activity performed and all were >10% with negative inhibitor screen (median 66%(26-100)). 24 patients (68.6%) had complement serology assessed. Three patients (12.5%) had low C3 while C4 was normal in 19 patients (79%). One patient in our cohort had complement mutational testing performed with no evidence of a pathogenic variant. Most common etiology of rTMA was medications (28.5%) and underlying rheumatologic disorder (20%)(Table 1). In 6 patients (17%), an identifiable cause was not elucidated. Management of TMA was dependent on underlying etiology of rTMA. Discontinuation or dose adjustment of TMA-causative medications was recommended in 4 patients and 25% of patients had normalization of Cr. Four patients received therapeutic plasma exchange (TPE) for median 5 (2-5) days. Causes of rTMA for those receiving TPE were gemcitabine, bevacizumab, unspecified connective tissue disease, and rTMA due to an unknown cause. 50% of patients were noted to have improvement in Cr with TPE. Antihypertensive medications were used for rTMA secondary to uncontrolled hypertension (n=4) and scleroderma (n=4). 11 patients (31%) were observed or treatment for causative underlying etiology was pursued, while 7 patients were treated with glucocorticoids. Of 6 patients, with no identifiable underlying cause, 4 were treated with observation, 1 was treated with GC, and one was treated with TPE Fourteen patients (38.9%) required dialysis; 6 of these patients were able to discontinue dialysis less than two months after initiation. Three patients (8.3%) with rTMA, respectively due to tacrolimus toxicity, longstanding hypertension, and systemic lupus erythematosus, received a renal transplant, and one additional pt (2.8%) with rTMA due to scleroderma remained on the renal transplant waiting list at time of death. In a median follow-up time of 8.73 months (range 0 to 47.9), 16 patients (44.4%) died. Median time from diagnosis of TMA to death was 12.1 months (range 1.47 to 58.2). No deaths were directly attributable to underlying TMA. Conclusion Renal-limited TMA is a pathologic diagnosis that in our cohort was most likely to medications or underlying rheumatologic conditions. rTMA was managed by treating the underlying disorder or removing the causative medication. Though cause of rTMA was evident in the majority of patients, 17% had no identifiable precipitating factor predisposing to rTMA. Larger studies are required to delineate optimal management and surveillance strategies for these patients. Disclosures No relevant conflicts of interest to declare.

Abstract Background/Objective: The association between paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size at disease onset and outcomes in patients with PNH remains unclear. Most but not all reports examining the relationship have shown a positive correlation between clone size and thrombotic events [TEs] in patients with PNH, but without a clear temporal association showing the prognostic value of clone size on the risk of TEs. The ongoing International PNH Registry (NCT01374360) is the largest prospective, observational study of patients with PNH conducted to date. The objective of this analysis was to examine the relationship between PNH granulocyte clone size at disease onset and risk of thrombosis after disease onset while untreated with a complement inhibitor in patients enrolled in the Registry. Methods: The current analysis included patients enrolled in the Registry as of April 2018 who had known demographics, were untreated with complement inhibitor therapy at enrollment, and had ≥12 months of untreated follow-up after disease onset. Baseline was defined as disease onset (earliest of a reported PNH clone, date of PNH diagnosis, or reported PNH symptom), and patients were stratified into 5 cohorts based on clone size at baseline (using the earliest reported clone prior to enrollment): cohort 1, clone size: 0.01-1%; cohort 2, clone size: >1-5%; cohort 3, clone size: >5-10%; cohort 4, clone size: >10-50%; cohort 5, clone size: >50%. Event rates for TEs and all major adverse vascular events (MAVEs; including TEs) were calculated for the time period from baseline to last follow-up. Other outcomes of interest included LDH ratio (LDH/LDH upper limit of normal [ULN]), hemoglobin levels, platelet counts, absolute neutrophil counts, and absolute reticulocyte counts at last follow-up. Results: A total of 2489 patients were eligible for the analysis. The majority of patients in the overall study population were female (54.0% [1343/2489]) and white (79.2% [1967/2484]). Mean (standard deviation [SD]) age at PNH start ranged from 36.4 (16.53) in cohort 5 to 44.2 (20.70) in cohort 1. Median time from baseline to last follow-up was 3.7 years in cohort 1, 4.3 years in cohort 2, 4.7 years in cohort 3, 5.6 years in cohort 4, and 6.8 years in cohort 5. Results for the outcomes of interest are summarized in the Table. All cohorts showed a risk of MAVE and TE during follow-up. Although estimated rates of MAVE and TE were highest in the >50% clone size cohort, there was no difference in the rate of MAVE or TE during follow-up across the 4 cohorts with clone size <50% at disease onset. Mean LDH ratio (LDH/LDH ULN) at last follow-up showed a statistically significant difference by clone size at baseline among the cohorts, ranging from a mean (SD) of 1.1 (1.34) in the patients with clone size <1% and increasing to 5.1 (3.81) in the patients with clone size >50% (P<0.0001). No difference in hemoglobin level at last follow-up was observed in the smaller clone size cohorts, although mean hemoglobin level was lower in patients with clone size >50% (P<0.0001). Similar trends were seen in mean platelet and absolute neutrophil counts across the smaller clone size cohorts, while patients with clone size >50% showed higher values (P<0.0001). Mean absolute reticulocyte count at last follow-up was lowest in patients with clone size 0.01-1%, and were incrementally higher in each successive clone-size cohort (P<0.0001). Conclusions: In this study, all patients with a PNH clone at disease onset were at risk for TEs and other MAVEs. Patients in the highest baseline PNH clone size strata (clone size >50%) had an approximately 2-times higher risk of TEs than patients with smaller clone sizes; Patients with small clone sizes (0.01-1%) were older and showed a higher prevalence of BMD. There was no difference in the prognostic value of clone size at disease onset on the risk of TEs and other MAVEs in patients with small (0.01-1% and 1-5%) versus medium-sized (5-10% or 10-50%) clones. Table Table. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Wilson:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Gustovic:Alexion Pharma GmbH: Employment, Equity Ownership. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria.

Abstract Introduction: Prognosis of AL amyloidosis has improved in recent years; however for many patients prognosis remains poor. We aimed to define patient-, disease- and treatment characteristics which are associated with long-term survival. Method: A retrospective chart review of all patients with biopsy-proven systemic AL amyloidosis, who were seen within 90 days of the confirmed diagnosis. Long-term survival was defined as 5-year and 10-year survival from the time of diagnosis. For 5-year survival we selected patients seen between January 1, 2000 and December 31, 2012 (allowing a minimum of 5-year follow-up, n=1331) and for 10-year survival we screened patients seen between January 1, 2000 and December 31, 2007 (allowing a minimum of 10-year follow-up; n=779). Treatment allocation was defined as the first regimen given, irrespective of subsequent treatment modifications. Results: Of the screening population, 498 patients survived ≥5 years from diagnosis (37% of the 5-year screening cohort) and 168 patients survived 10 years or more (22% of the 10-year screening cohort). Five-year survivors and 10-year survivors as compared to their counterparts were (Table): younger, higher proportion of women, more likely to have single organ involvement, less heart/liver/nerve involvement and more kidney involvement. Long-term survivors also had lower bone marrow plasma cell percentage at the time of diagnosis and lower tumor burden measured by the difference between involved to uninvolved light chain (dFLC). Similarly, long-term survivors had lower Mayo stages and higher systolic blood pressure. No difference in light chain isotype was observed between long-term survivors to long term non-survivors. Long-term survivors were less likely to be seen within 30 days of diagnosis compared to their counterparts (52% among 5-year survivors vs 67% among 5-year non-survivor; P<0.001). FISH abnormalities (data available for 555/1331 patients, 42%) were comparable between groups with regard to t(11;14) (50% among 5-year survival compared to 50% among 5-year non-survivors; P=0.93) and 13q abnormalities (34% vs 36%, respectively; P=0.53). However, trisomies were less frequently encountered in the 5-year survivor group (20% vs 29%, respectively; P=0.01), and far less common among 10-year survivors (11% vs 26%, respectively; P=0.04). Autologous stem cell transplantation (ASCT) was more likely to be associated with long-term survival. Of all patients who underwent ASCT, 74% survived more than 5 years and 49% survived more than 10 years. In comparison, among the standard-intensity therapies, 5-year survival rates for melphalan-dexamethasone, bortezomib-based regimens, immunomodulatory drug-based regimens and single agent dexamethasone/ melphalan-prednisone were 29%, 28%, 30% and 10%, respectively. The corresponding 10-year survival rates were 15%, 20%, 20% and 5%, respectively. Conclusions: Long-term AL survivors have distinct favorable baseline characteristics (including those introduced by referral bias) and ASCT as their initial therapy. Identification of these patients, especially the Mayo 2004 stage III and the Mayo 2012 stage III-IV patients who unexpectedly survived 10 years, will allow for further study and insights. Disclosures Gertz: Teva: Consultancy; Prothena: Honoraria; Alnylam: Honoraria; celgene: Consultancy; Ionis: Honoraria; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; janssen: Consultancy; Apellis: Consultancy; Medscape: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; annexon: Consultancy. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Kumar:KITE: 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, Research Funding; Novartis: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: 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, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; AbbVie: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract Background: The introduction of several novel agents has led to an improvement in response rates and survival outcomes in patients with newly diagnosed multiple myeloma. Despite significant therapeutic advances a subset of patients with multiple myeloma do not achieve a deep response to first-line treatment and biomarkers are needed to identify those at risk. Methods: We studied 472 patients with newly diagnosed multiple myeloma who were treated in clinical practice (n = 280, training cohort) or on prospective clinical trials (n = 192, validation cohort) at Mayo Clinic between 12/2003 and 12/2015. All patients had measurable disease (M-spike ≥ 1.0 g/dL) and received treatment with novel agents. Serum M-spike and free light chains (FLC) were measured before and after the first treatment cycle. The outcome of interest was the best response to first-line treatment (evaluated using the International Myeloma Working Group Uniform Response Criteria). Failure to achieve a deep response was defined as not achieving a very good partial response or better. The serum parameters of interest were the relative decrease in M-spike and absolute free light chain difference (ΔFLC). The Wilcoxon signed-rank test was used to compare the serum parameters before and after the first treatment cycle. Logistic regression models were used to assess the associations between the change in serum parameters after the first treatment cycle and best response to first-line treatment. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis in the training and the validation cohort were 67 (32 - 94) and 66 years (41 - 86), respectively. One hundred eighty one (65%) and 103 patients (54%) were male, respectively. The three most common regimens in the training cohort were lenalidomide + dexamethasone, lenalidomide + cyclophosphamide + dexamethasone, and bortezomib + lenalidomide + dexamethasone. In the validation cohort, the three most common regimens were carfilzomib + thalidomide + cyclophosphamide, lenalidomide + cyclophosphamide + dexamethasone, and ixazomib + cyclophosphamide + dexamethasone. In the two cohorts, the median baseline M-spike decreased from 3.1 g/dL (1.0 - 10.0) to 1.7 g/dL (0.0 - 6.6) and 3.2 g/dL (1.0 - 8.5) to 1.4 g/dL (0.0 - 4.5) after the first treatment cycle, respectively (p < 0.001 for both comparisons). The median baseline ΔFLC decreased from 31.1 mg/dL (0.0 - 2269.7) to 5.4 mg/dL (0.0 - 785.8) and from 23.3 mg/dL (0.1 - 3579.6) to 4.3 mg/dL (0.0 - 1139.3) after the first treatment cycle, respectively (p < 0.001 for both comparisons). M-spike reduction < 50% during the first treatment cycle was associated with failure to achieve a deep response: OR 4.54 (95% CI 2.72 - 7.58, p < 0.001) in the training cohort and OR 6.68 (95% CI 3.42 - 13.03, p < 0.001) in the validation cohort. Patients with reduction in M-spike < 10% during the first treatment cycle experienced failure to achieve a deep response in 86% (25/29) and 100% (10/10), respectively. ΔFLC reduction < 50% during the first treatment cycle was associated with treatment failure to achieve a deep response: OR 4.83 (95% CI 2.83 - 8.25, p < 0.001) in the training cohort and OR 5.09 (95% CI 2.37 - 10.92, p < 0.001) in the validation cohort. Patients with reduction in ΔFLC < 10% during the first treatment cycle experienced failure to achieve a deep response in 83% (34/41) and 91% (19/21), respectively. Conclusions: Early changes in M-spike and ΔFLC are strong predictors of response to treatment. We established and prospectively validated two readily available biomarkers that can identify patients at risk for treatment failure and may inform treatment decisions in newly diagnosed multiple myeloma. Disclosures Lacy: Celgene: Research Funding. Gertz:Physicians Education Resource: Consultancy; janssen: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; Medscape: Consultancy; annexon: Consultancy; Abbvie: Consultancy; celgene: Consultancy; Prothena: Honoraria; Ionis: Honoraria; Amgen: Consultancy; spectrum: Consultancy, Honoraria. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: 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; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: It is well known that the staging stratification at diagnosis predicts survival in immunoglobulin light chain (AL) amyloidosis, but there is a paucity of literature delineating the prognostic value of these systems at the time of 2nd-line therapy. Methods: We conducted a retrospective study to evaluate the prognostic value of AL staging among 563 patients with staging data, who initiated a 2nd-line therapy between 2000 and 2015. Both the Revised Mayo 2012 staging system and the European revision of the Mayo 2004 staging system were used. Results: The median time from initial treatment to 2nd-line therapy was 11.6 months. Median follow-up from institution of 2nd-line therapy was 54.1 months. The 1st-line therapy for patients was autologous stem cell transplant (ASCT) in 216 (38%) patients; and 2) non-ASCT therapies in 347 patients. Both staging systems were prognostic with a risk ratio of 9.4 (95%CI: 6.0, 15.1; p<0.0001) between stage IIIb and I, and of 12.2(8.1, 18.5; p<0.0001) between IV and I. At the time of 2nd-line therapy the staging systems' predictive values were independent of what the patients' 1st-line therapies had been despite the fact that the median time from initial treatment to 2nd-line therapy was 19.4 months in ASCT group and 8.0 months in non-ASCT group. Among the patients receiving 2nd-line therapy after ASCT, the 5-year overall survival (OS) from 2nd-line therapy for those with ≤ stage II versus >stage II was 65% and 31% (Mayo 2004) and 70% and 23% (Mayo 2012). The respective numbers for patients relapsing from a non-ASCT therapy were 57% and 26% (Mayo 2004) and 60% and 23% (Mayo 2012). Conclusions: This study indicates that the Mayo staging systems work well at the time of instituting 2nd-line therapy and is independent of whether 1st-line therapy was ASCT based. Figure. Figure. Disclosures Gertz: annexon: Consultancy; Medscape: Consultancy; Apellis: Consultancy; celgene: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; spectrum: Consultancy, Honoraria; Ionis: Honoraria; Research to Practice: Consultancy; Teva: Consultancy; janssen: Consultancy; Alnylam: Honoraria. Kumar:KITE: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Russell:Vyriad: Equity Ownership. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding.

Abstract The use of soluble cardiac biomarkers such as NT-proBNP and troponin has revolutionized prognostication for patients with AL amyloidosis and led to their use in the Mayo 2004 and 2012 staging systems. Novel soluble markers with different phenotypic targets may further improve this approach. Soluble ST2 (sST2), which is the circulating form of the IL-33 receptor, has been shown to be a marker of cardiac remodelling and fibrosis, is predictive of mortality in patients with congestive heart failure, and is predictive of risk of GVHD and GVHD mortality. Samples of blood of patients with AL amyloidosis collected and frozen at -20C under a biobank IRB protocol were retrieved and sST2 measured. Patients were eligible for present study if they had a research sample collected within 90 days of their AL amyloidosis diagnosis. We have validated that values do not change significantly with storage at -20C over a 90 day period. Concentrations of sST2 were determined using a novel high-sensitivity sandwich immunoassay (Presagew ST2; Critical Diagnostics, San Diego, CA, USA). The sST2 assay had within-run and total coefficients of variation of <7.5% and 13.0% across its measurement range. Samples from 273 consecutive patients meeting diagnostic criteria for AL amyloidosis seen at our institution from 1/9/2010 to 12/22/2011 were evaluated. Median age was 63. 58% were male. One hundred and thirty have died over 33.9 months. Correlation between sST2 and the other biomarkers was modest with correlation coefficients of 0.48 and 0.20 for NT-proBNP and Troponin T, respectively. Patients with sST2 above and below the median of 27.2 ng/mL (6.3-596) had significant differences in 2 year overall survival: 71.2% to 39% (figure). In multivariate modeling sST2’s prognostic value was independent of the Mayo 2004 and the Mayo 2012 cardiac biomarker staging systems, the latter of which also includes prognostic information relating to plasma cell burden. In these multivariate models, sST2 median had a RR of 2.4, (95%CI 1.6, 3.6 p<0.001) with the Mayo 2004 Staging system (RR of 2.9, 95%CI 2.1, 4.1p<0.001); and sST2 median had a RR of 2.2 (95%CI 1.5, 3.4, p<0.001) with the Mayo 2012 staging system (RR 1.9, 95%CI 1.6, 2.3, p<0.001). A larger cohort including patients with longer follow up will be presented at the meeting as will gender specific cut off values and a comparison of our values with those previously used to prognosticate in patients with heart failure. sST2 appears to be a novel powerful prognostic factor for patients with AL amyloidosis. Because sST2 functions as a decoy receptor, which neutralizes the benefits of IL-33, it may play a role in the deleterious phenotype seen in patients with AL, i.e. myocardial hypertrophy and reduction of contractility. Disclosures: Saenger: Critical Diagnostics : Research Funding; Roche: Research Funding. Jaffe:Critical Diagnostics: Consultancy, Research Funding; Roche: Consultancy.

Abstract Context and objective Approximately 5-10% of diffuse large B-cell lymphoma (DLBCL) patients carry MYC gene translocations (MYC-translocation+) with a poor prognosis after standard chemotherapy. MYC-translocation+ DLBCL patients carrying BCL2 translocations (MYC+/BCL2+ double-hit lymphoma) have a worse survival. The efficacy of adjuvant radiotherapy in this setting is unknown. The purpose of this study is to evaluate the efficacy of radiotherapy as a part of the therapeutic regimen for patients with MYC-translocation+ DLBCL. Patients and methods From the International DLBCL R-CHOP consortium program, we selected 581 patients with de novo DLBCL treated with standard R-CHOP immunochemotherapy (diagnosed and treated from 2000 to 2010). We excluded patients with transformed DLBCL, primary mediastinal, cutaneous, testicular or central nervous system large B-cell lymphomas, patients with HIV infection, and patients not treated with R-CHOP. The median follow-up was 54.9 months. Fluorescence in situ hybridization assessing MYC was performed for all the patients (n=581) and results were correlated with available clinical data to identify clinicopathologic features associated with MYC translocation, and to evaluate the prognostic significance of MYC translocations regarding overall survival (OS, from the time of diagnosis to death from any cause) and progression-free survival (PFS, from the time of diagnosis to relapse or death from any cause). In the MYC-translocation+ DLBCL group, 38 patients received chemotherapy alone and 21 patients received chemotherapy with adjuvant radiation therapy. The clinicopathologic features and survival of MYC-translocation+ DLBCL patients treated with (n=21) and without radiotherapy (n=38) after immunochemotherapy were compared to in order to evaluate the radiotherapy efficacy and other confounding factors. Results MYC translocations were detected in 59 DLBCL patients (10.2%). Patients with MYC-translocation+ DLBCL more often had bulky tumors, involvement of multiple extranodal sites, and poorer OS (hazard ratio [HR]: 2.0, 95% confidence interval [CI]: 1.20 - 3.35, P= .0083) and PFS (HR: 1.96, 95% CI: 1.22 - 3.13, P= .0005) independent of the International Prognostic Index score. Poor survival was primarily attributable to patients with MYC+/BCL2+ double-hit DLBCL who were predominantly of germinal center B-cell subtype. Among MYC-translocation+ DLBCL patients, a better survival was achieved in patients who received radiotherapy (for OS, HR: .32, 95% CI: .15 - .71, P= .0049; for PFS, HR: .35, 95% CI: .17 - .73, P= .0043). Conversely, radiotherapy abolished the adverse impact of MYC translocations. In addition, radiotherapy was associated with better survival in the subset of patients with MYC+/BCL2+ double-hit lymphoma (P = .017 for OS, and P = .05 for PFS). However, owing to the common use of radiotherapy as consolidation therapy, the favorable prognoses in the group of patients who received radiotherapy could also be attributed to limited-stage disease and more frequent complete remission (CR) after first-line treatment and therefore these factors confound interpretation of the data. To address these issues, we evaluated radiotherapy efficacy in separate patient groups: patients who achieved CR, non-CR (PR/SD/PD) patients, and patient with stage I/II, or stage III/IV disease. The efficacy of radiotherapy appeared more apparent in patients with advanced disease who did not achieve CR after first-line chemotherapy. Multivariate analysis after adjustment for stage and IPI score validated that radiotherapy significantly improved OS (HR: .28, 95% CI: .10 - .81, P= .018) and PFS (HR: .32, 95% CI: .13 - .80, P= .015) of MYC-translocation+ DLBCL patients. Conclusions The presence of MYC translocations in DLBCL is an important biomarker that facilitates prognostic prediction and treatment stratification independent of the IPI score. For chemoresistant MYC-translocation+ DLBCL patients, radiotherapy seems to be an effective adjuvant regimen likely due to the higher frequency of extranodal involvement and bulky disease in MYC-translocation+ DLBCL patients. Our results provide a rationale for larger scale studies to assess the potential role of radiotherapy in the management of MYC-translocation+ DLBCL patients, particularly patients with MYC+/BCL2+double-hit DLBCL. Disclosures: Winter: Millenium: Research Funding; Novartis : Research Funding; Pfizer (Wyeth): Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Janssen (Pharmacyclics): Research Funding; Spectrum (Allos): Consultancy; Sanofi Aventis: Consultancy; Tgen: Consultancy; AMBIT Biosciences (Spouse): Research Funding; Celgene (Spouse): DSMB, DSMB Other, Research Funding; Ariad Pharmaceuticals (Spouse): Research Funding; Novartis (Spouse): Consultancy, Research Funding; Amgen (Spouse): Consultancy, Research Funding; Astellas (Spouse): Research Funding; Caremark/CVS: Consultancy; Pfizer (Spouse): Consultancy; Sanofi Aventis (Spouse): DSMB, DSMB Other; Bristol Myers Squibb (Spouse): DSMB, DSMB Other; UptoDate, Inc.(Spouse): Patents & Royalties.