ALBERT

Description: Abstract 3124 Background: The incidence of NHL increases exponentially with rising age. The most rapidly growing segment of the population is persons 〉 age 65 years, especially 〉 age 80. As a percentage of US population, the age group 〉80 years has increased by 〉250% from 1960 to 2000. Furthermore, persons 〉80 years will more than double within 20 years. However, little data is available regarding the characteristics or outcomes of very elderly NHL patients (pts). Methods: We completed a multicenter retrospective analysis of very elderly NHL pts (=/〉 80) diagnosed (dx) between 9/99-9/09 at 4 Chicago centers. Detailed pt and disease characteristics were collected including comorbidities, which were assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Pts were also classified if they were “fit” (i.e., preserved activities of daily living (ADLs), 1 extranodal 20%, elevated LDH 38%, anemia 41%, thrombocytopenia 16%, renal insufficiency 25%, and 36% had a history of coronary artery disease. Additionally, 28% had prior malignancy. Comorbidities were common; 77% of pts had a cumulative CIRS score 〉6, while 74% had a grade 3–4 CIRS-G in at least 1 category. Furthermore, 33% were classified as “not fit” at NHL dx, 12% had loss of ADLs, while 22% had a geriatric syndrome at time of NHL dx. 57% had stage III/IV disease. Pts with aggressive B cell histology received a rituximab (R)-containing regimen 85% of the time, while 84% of all aggressive NHL received at least one cycle with an anthracycline. Initial therapy for B cell indolent NHL were: observation (24%), R alone (35%), R-chemotherapy (CT) (31%), radiation (8%), and CT alone (2%). Among all pts, the overall response to first treatment was 68% (CR 49%). With 40-month median follow-up (1-120), 3-year EFS (event-free survival) and OS (overall survival) for all pts were 43.8% and 70.3%, respectively (stage I/II: EFS 49% and OS 81%; stage III/IV: EFS 42% and OS 65%; p=0.039 and p=0.09, respectively). Among aggressive NHL (n=74), 3-year EFS and OS were 55% and 64% (stage I/II: EFS 86% and OS 94%; stage III/IV: EFS 45% and OS 57%; p=0.0006 and p=0.03, respectively), while for indolent NHL (n=76), the 3-year EFS and OS were 34% and 77%, respectively (Figures 1–3). Prognostic factors predicting survival are shown in Table 1. In multivariate regression analyses, no response to initial therapy (i.e., SD/PD) predicted for significantly inferior EFS and OS (HR 5.45 [2.02-13.65], p=0.0007 and HR 6.88 [1.66-28.44], p=0.008, respectively). Conclusion: Long-term survival of very elderly NHL was feasible with 64% and 77% 3-year OS for aggressive and indolent histologies, respectively. However, comorbidities as well as a designation of “unfit” portended a significantly inferior outcome in univariate models. Primary resistance to initial therapy occurred in 32% of pts and also predicted for poor prognosis. Given the rising incidence and prevalence of very elderly NHL, prospective examination of this subset of pts is strongly warranted. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Peripheral T-cell lymphomas (PTCL) are a rare heterogeneous group of lymphoid malignancies, which originate from post-thymic (or mature) T-cells. Although there are approximately 7,000 new cases of PTCL in the US annually, PTCL is extremely heterogenous and difficult to diagnose even in academic settings (Teras et al. 2016. CA Cancer J Clin 2016; 66:443-459). Prior research suggests a high rate of diagnostic revision among PTCL patients. The objective of this analysis was to describe the rate of diagnostic revision among patients with a PTCL diagnosis using 2 large, real-world US databases. Methods: This retrospective analysis used the IBM MarketScan Commercial and Medicare Supplemental administrative claims databases (claims) and the IBM Explorys Research Database, an electronic health record (EHR) database; both databases have national coverage but are fundamentally different in their structure and data sources. Adults (age ≥18 years) with a new diagnosis of PTCL between January 2010 and June 2017 were identified in each database. The prevalence of diagnostic revision was the primary outcome, defined as the diagnosis of a non-PTCL diagnosis before or after the PTCL diagnosis with the latest diagnosis serving as the index date. Other lymphomas included were Hodgkin's, diffuse large-B-cell (DLBCL) and marginal zone lymphoma. The presence of anaplastic large cell lymphoma, mature T/NK-cell lymphomas, and other subtypes of T/NK-cell lymphomas closely related to PTCL were described but were not classified as diagnostic revision. Patients were required to have 12 months of pre-index and one month of post-index continuous enrollment (claims) or evidence of database activity (EHR). Results: 2561 patients met the selection criteria for the claims database analysis (mean age 59.9 [SD=15.4]; 42.9% female) and 1,881 met the EHR criteria (mean age 64.3 [SD=15.2]; 47.0% female). Diagnostic revision was present among 29.3% of PTCL patients in the claims analysis and 21.6% of PTCL patients in the EHR analysis. Among patients with diagnostic revision, 51.4% revised to PTCL and 48.6% revised from PTCL in the claims analysis, while 56.0% revised to PTCL and 44.0% revised away from PTCL in the EHR analysis. Among patients with diagnostic revision from PTCL, 37.5% were revised to DLBCL, 17.0% revised to Hodgkin's disease, and 4.9% to marginal zone lymphoma in the claims analysis, and 42.5% revised to DLBCL, 10.6% revised to Hodgkin's disease, and 7.9% to marginal zone lymphoma in the EHR analysis. Among patients with diagnostic revision to PTCL, 32.0% revised from DLBCL, 14.9% revised from Hodgkin's disease, and 5.2% from marginal zone lymphoma in the claims analysis, and 34.6% revised from DLBCL, 11.1% revised from Hodgkin's disease, and 10.3% from marginal zone lymphoma in the EHR analysis. The average time from the first diagnosis to the final diagnosis in the 12-month baseline period was 150.9 [SD=128.2; median 122.5] days in the claims analysis and 167.4 [SD=127.6; median=128.5] days in the EHR analysis (Table 1). Baseline Deyo Charlson Comorbidity Index scores were higher among patients with diagnostic revision in both the claims (4.1 [SD=2.8] vs. 2.8 [SD=2.5]) and EHR (2.4 [SD=2.5] vs. 4.4 [SD=3.1]) analysis (both p

Description: Introduction: Treatment of relapsed or refractory classical Hodgkin lymphoma (R/R cHL) in patients considered ineligible for stem cell transplant (SCT) in the United States (US) has evolved since 2011. It is important to understand the current treatment landscape and the outcomes associated with current standards of care as new treatment options have been introduced. This analysis provides recent real-world evidence on patient characteristics, treatment patterns, and outcomes in R/R cHL patients in the US who are initially considered ineligible for SCT and are treated with or without brentuximab vedotin (BV). Methods: Hematologists and oncologists (N=205) from the US retrospectively identified patients diagnosed with R/R cHL who received at least two lines of therapy and received their most recent line of therapy between January 2014 and May 2018. The physicians were responsible for abstracting data and completing response forms for variables of interest. The current analysis focused on patients who were considered ineligible for SCT by their physician: descriptive statistics on patient demographics/clinical characteristics, treatment patterns, and outcomes by line of therapy; bivariate analyses (chi-square) comparing treatment modalities by line of therapy. Results: Physicians retrospectively identified 297 patients that they considered ineligible for SCT. Mean (SD) age at initial cHL diagnosis was 53.0 (18.5), most patients were male (69.4%) and Caucasian (61.3%). The most common cHL subtype at diagnosis was nodular sclerosis HL (40.4%), and patients had either Stage I/II (45.8%) or Stage III/IV (54.2%) cHL at initial diagnosis. Median follow-up time for the cohort included here was 15.96 months from initiation of 1L treatment. The majority of the cohort (N = 297) received systemic therapy alone (84.5%) compared to those who received systemic therapy in combination with radiation therapy (RT) (15.5%) in 1L. 1L systemic regimens included regimens that contained ABVD alone or ABVD in combination with other regimens (69.4%). Of those who used ABVD alone or in combination with another regimen (N = 206), 24.8% used a PET adapted approach and deescalated to AVD (N = 51) and 11% escalated to be BEACOPP (N = 18). Other systemic regimens included AVD (10.1%), BEACOPP (7.4%) and ICE (5.7 %). The majority of patients achieved a complete response (CR) or partial remission (PR) after 1L therapy (41.4%, 38% respectively) while 34.1% (N = 61) failed to achieve remission or progressed while on therapy. The most common systemic regimens in 2L (N = 293) were BV monotherapy or in combination with bendamustine (34.6%), salvage regimens [including ICE, DHAP, ESHAP or gemcitabine based combinations] (33%), re-challenge with a previous 1L regimen (19.5%), and PD-1 inhibitors (10.8%). Very few patients received systemic therapy in combination with RT (6.7%) in 2L.The most common systemic regimens used in 3L (N = 21) for the selected cohort of patients not eligible for SCT were BV monotherapy (28.6%) and PD-1 inhibitors (33.3%). Median (range) number of cycles in 2L and 3L was four (1-18) and two (1-14), respectively. Treatment outcomes were variable for patients in 2L and 3L. In 2L, 27.6% achieved a CR, 25.6% achieved a PR, while 24.2% and 15.8% were refractory or progressed on treatment. There were no CRs reported in 3L (N = 21). 26 patients died in 2L and 3L combined. Conclusion/Summary: Given the rapid evolution of therapies used to treat R/R cHL, these findings fill a crucial data gap in real-world evidence on patient characteristics, treatment patterns, and outcomes of patients deemed SCT ineligible in the US. Disclosures Feliciano: Seattle Genetics: Employment. Way:Kantar Health: Employment; Seattle Genetics: Research Funding. Engley:Seattle Genetics: Employment. Ghosh:Juno: Consultancy, Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; PCYC: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Spectrum: Consultancy; Gilead: Consultancy, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; Genentech: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Abbvie: Consultancy, Speakers Bureau; Forty seven Inc: Research Funding; TG Therapeutics: Honoraria, Research Funding.

Description: Background. Previous studies have suggested a variation in the incidence of acute promyelocytic leukemia (APL) among geographic regions with relatively higher percentages within the Latin American population. We aimed to describe the population burden of pediatric APL (p-APL) in Brazil assessing the incidence rates according to a hospital-based and population-based cancer (PBCR) registries. We also explored mutations in genes of the RAS pathway and the association of polymorphisms in genes of glutathione S-transferases (GSTs) with outcome. Our goal was to provide insights into the distribution of clinical-demographic data and the molecular epidemiology characteristics associated with APL outcome. Methods. One hundred and sixty-four p-APL cases (2-10 and 〉10-21 years old (43.3% and 51.8%, respectively) and sex. RAS mutations were observed in 51.7% of APLs, including FLT3 (43.0%), NRAS (6.5%), and KRAS (2.2%). Variants in PTPN11 were silent amino acid substitutions (rs61736914; 4.9%). We observed a statistically significant association between FLT3 mutations and high white blood cell count at diagnosis (〉10x109/L; 72.6%), low platelet count (70%). Disclosures No relevant conflicts of interest to declare.

Description: Introduction: The majority of PTCL cases are pathologically heterogeneous, aggressive and chemorefractory; nearly 70% of patients who undergo induction chemotherapy develop RR disease. Data on how RR-PTCL patients are managed outside of clinical trials and academic settings have not been adequately studied. Understanding how PTCL patients are treated in the real world allows better design of future clinical trials and refined development of novel therapies. This study aimed to describe contemporary treatment patterns, clinical characteristics, and overall survival (OS) among RR-PTCL patients treated in the US community oncology setting. Methods: We conducted a retrospective, observational cohort study of RR-PTCL patients treated between 1/1/2010-12/31/2016. Data were collected from patient medical records abstracted from 30 community oncologists across all geographic areas in the US (38% South, 22% West, 7% Midwest, 26% Northeast, and 7% unknown). Patient characteristics, treatment patterns, adverse events (AEs), physician-reported response to first- and second-line (1L, 2L) treatments, and date of death were collected. Descriptive statistics were calculated to summarize patient characteristics and study outcomes. Median (95% confidence interval [CI]) OS from RR disease was calculated by the Kaplan-Meier method. Results: We analyzed 200 RR PTCL patients (71% received CHOP, 20% received CHOEP, and 9% received another regimen as 1L systemic therapy). The majority (58%) were PTCL not otherwise specified (NOS), 61% were males, and median age was 62 years (range: 20-90) (Table). Overall response rate (ORR) to 1L treatment was 80% (CR, 54%; PR, 26%), and ORR to 2L treatment was 55% (CR, 31%, PR, 24%). Among all PTCL patients and among those with PTCL NOS, the OS (95% CI) from RR disease was 13.0 months (95% 7.0-not estimable) and 9.0 months (95% 6.0-not estimable), respectively (Figure). Median time to RR disease from 1L initiation was 12.9 months. Median durations of 1L and 2L treatments were 4.4 months and 3.7 months, respectively. Among those who continued to 2L therapy, 27% received brentuximab vedotin (2% in combination), 19% received ICE (carboplatin/cisplatin, ifosfamide, etoposide), 13% received romidepsin (2% in combination with pralatrexate), 10% received pralatrexate monotherapy, 7% received GEMOX (gemcitabine, oxaliplatin), and the rest (22%) received other 2L regimens or an unknown regimen (2%). After 1L initiation, only 14/200 (7%) received hematopoietic stem cell transplant (HSCT) and 28/151 (19%) after 2L. AEs resulting in a dose reduction, discontinuation, or hospitalization during 1L treatment and occurring among ≥10% included anemia (39%), thrombocytopenia (27%), neutropenia (23%), mouth sores (16%), diarrhea (15%), neuropathy (14%), febrile neutropenia (13%), and vomiting (10%). Conclusions: While response to 1L treatment in this cohort was high (80%), all developed RR disease (or died), for whom the prognosis remains poor. Very few patients underwent HSCT in any line of therapy. Our data demonstrate the unmet medical need for RR-PTCL patients and the need for novel therapies in the 1L setting. It also underscores the need to better understand factors leading to treatment selection and optimal treatment sequencing in the real world. Disclosures Nabhan: Cardinal Health: Employment, Equity Ownership. Laney:Cardinal Health: Employment, Equity Ownership. Feliciano:Seattle Genetics: Employment, Equity Ownership. Lee:Cardinal Health: Employment. Klink:Cardinal Health: Employment, Equity Ownership.

Description: Leukemias containing Mixed Lineage Leukemiagene rearrangement (MLL-r) account for 5-10% of human acute leukemia cases and are associated with a poor prognosis. The unmet clinical need and the lack of an effective targeted therapy emphasizes the need for novel approaches for these malignancies.Recent studies have discovered an essential role for the histone H3 lysine 79 (H3K79) methyltransferase DOT1L in the maintenance of MLL-r leukemias. Phase-I clinical trials (NCT01684150 and NCT02141828) have demonstrated the safety and clinical activity of the DOT1L-specific small molecule inhibitor EPZ5676 (Pinometostat, Epizyme Inc.). However, the variable response of the MLL-r patients in these clinical trials indicates the need to further understand the mechanism of action and resistance to DOT1L inhibitors. To address this issue, we designed a high-density CRISPR screen approach (Fig 1) to dissect the function of Dot1l coding regions in mouse MLL-AF9 leukemic cells, a well-established mouse model that mimics human MLL-r acute myeloid leukemia (AML). We constructed a library of 602 sgRNA that targets most of the "NGG" protospacer adjacent motifs (PAM) within Dot1l exons. The average targeting density is 7.7 bp per sgRNA (i.e. 2.5 a.a. per sgRNA). We delivered this sgRNA library into Cas9-expressing MLL-AF9 AML cells using lentiviral transduction, and then compared the frequencies of each integrated sgRNA sequence before vs. after 12 days of culture using high-throughput sequencing (NextSeq, Illumina Inc.). The results revealed a significant depletion of clusters of sgRNA targeting the known functional regions including the lysine methyltransferase (KMT) core and the AF9-binding domains of DOT1L. We mapped the CRISPR scan score to the previously solved three-dimensional structures of DOT1L and found the high-density CRISPR scan clearly distinguishes the substrate binding pocket from the less important regions within the KMT domain. Furthermore, we identified CRISPR hotspots that coincide with amino acid residues directly contacting the enzymatic substrate S-adenosylmethionine (SAM). Similarly, CRISPR scan identifies amino acid hot spots in DOT1L that establish a direct interaction with the cofactor AF9. These results implicate the utility of the high-density CRISPR scan to pinpoint the functional elements within a protein to a sub-domain resolution. To identify regions in DOT1L that mediate response of MLL-r leukemia to DOT1L-inhibitors, we conducted parallel CRISPR scans by culturing the Dot1l sgRNA library transduced MLL-AF9-Cas9+cells in either DMSO (vehicle) or the DOT1L inhibitor (1 uM EPZ5676) for 12 days. These paired screens revealed distinct patterns of the CRISPR scan scores between the two culture conditions. Surprisingly, a cluster of 31 sgRNA targeting the amino acid residues T560 - S661 of DOT1L was significantly enriched only in the presence of the DOT1L inhibitor.Expression of individual sgRNA targeting this region confirmed the EPZ5676-resistant phenotype observed in the CRISPR scans. Computational modeling of the structure of DOT1L suggests this newly identified region overlaps with two alpha-helixes motifs in a predicted coiled-coil domain. Finally, we examined eight clinically observed DOT1L missense mutations in this region (cBioPortal database; 54,510 patients) and foundthree DOT1L-mutant constructs (A591V, G594S and L626P) when expressed in the MLL-AF9 leukemia cells can confer resistance to EPZ5676. These findings suggest the utility of the high-density CRISPR scan for de novoidentification of drug-resistant mutant alleles in the human population, which maydirect future clinical decisions and benefit patients with specific genomic backgrounds. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Most existing cancer registries do not fully capture relapse or progression of cancer. Further, clinical trials for upfront treatment typically withdraw patients from study at the time of treatment failure and only collect minimal information about approaches to and outcomes with salvage therapy. As such, patient outcomes other than mortality often are available only through formal chart review, which is resource intensive. For HL, although many patients are successfully cured, a sizeable subset of patients experience treatment failure. Most of the data describing failure arises from prospective clinical trials, despite most patients receiving treatment in the community setting. Therefore, data from the community setting are needed to understand the experience of real-world patients and to inform and improve the quality of care in oncology practices. To facilitate observational research and quality improvement projects on HL treatment failure, we examined an EHR-based algorithm for identifying treatment failure in HL. Methods All HL patients who initially presented with advanced stages II-IV disease between 2007-2012 at Kaiser Permanente Southern California (KPSC) were identified using KPSC's cancer registry. An algorithm for identifying treatment failure was proposed by study oncologists. Treatment failure was defined as relapse after complete remission of 〉 60 days' duration or disease progression on active treatment. The algorithm was defined as meeting one of the following: (1) Initiation of any second chemotherapy regimen, including use of brentuximab vedotin, or PD-1 inhibitor beyond initial regimen; or (2) stem cell transplantation (SCT). Data needed to construct the algorithm were collected from KPSC's EHR, including the chemotherapy database and transplant registry. The algorithm was applied to all HL cases up to 4 years after diagnosis, as most HL relapses occur within this timeframe. Manual chart reviews were performed for all potential treatment failure cases identified by the algorithm, and for one-third of randomly-selected HL cases not captured by the algorithm. Each case was abstracted by trained study staffed and reviewed for quality control by two study oncologists. Results Of the 470 HL patients newly diagnosed during the study period (91% diagnosed at age 18 and older, 57% male), the algorithm identified 80 as potential treatment failure cases. Chart review confirmed 75 of 80 as actual treatment failure. The algorithm misclassified relapse for 5 cases who had emergence of a second malignancy for which therapy was instituted after the completion of initial therapy for HL. The positive predictive value (PPV) was 94% (95% confidence interval: 89%-99%). The negative predictive value (NPV) based on the review of 127 patients not captured by the algorithm was 100%. Based on the high PPV and NPV, our review suggested both a high sensitivity and specificity of the algorithm. Conclusion This EHR-based algorithm, based on receipt of second-line therapy beyond initial treatment and SCT, was highly effective in capturing relapse or disease progression cases among HL patients in this integrated health care delivery system. Application of this algorithm will allow for better long-term follow up for novel agents in observational studies, which is critical for understanding the cost-effectiveness of therapeutic agents in real-world patients. External validation using data from other health care settings or sources such as claims data will be useful to further confirm the generalizability of this algorithm. Altogether, this algorithm could assist practices in the identification and prospective tracking of the relapsed/refractory HL patient population for clinical and non-clinical outcomes, such as cost, health-related quality of life, and sequelae of treatment. Disclosures Chao: Seattle Genetics: Research Funding. Xu:Seattle Genetics: Research Funding. Cannizzaro:Seattle Genetics: Research Funding. Rodday:Seattle Genetics: Research Funding. Feliciano:Seattle Genetics: Employment, Equity Ownership. Kumar:Seattle Genetics: Research Funding. Evens:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Tesaro: Research Funding; Abbvie: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Novartis: Consultancy; Acerta: Consultancy; Bayer: Consultancy. Parsons:Seattle Genetics: Research Funding.

Description: Abstract 3990 Poster Board III-926 Background In 2005, the first ever Citizen Petition filed by a State Attorneys General, Attorney General Richard Blumenthal, requested that the FDA adopt 6 measures to improve VTE prophylaxis and patient safety of thalidomide (thal). While 4 recommendations were accepted, the FDA refused to mandate a Phase IV randomized, controlled trial designed to identify the best VTE prophylaxis stating that substantial data already existed, but no specific prophylaxis was identified. We review the progress of this safety concern pre- and post-FDA approval of thal in 2006, specifically for the use of multiple myeloma patients. Similar safety concerns apply to lenalidomide. Methods A literature search was performed from 2006 to 2009 through Pubmed and Ovid using the key words “thalidomide,” “lenalidomide,” “thrombosis,” and “multiple myeloma.” High dose thal was defined as higher than 200mg/d, low dose thal as 200mg/d or lower, and high dose dexamethasone (dex) as higher than 20mg/d and low dose dex as 20mg/d and lower. Results See table Conclusion Since 2006, we have found information on 2657 patients with no prophylaxis, 539 patients with thal/dex with prophylaxis, and 2210 patients with len/dex with prophylaxis. VTE rates remain high, except for the low dose thal and/or low dose dex group. Overall, optimal VTE prophylaxis remains an enigma. Current recommendations for VTE prophylaxis are not supported by empirical data. Against this backdrop, Blumenthal's team should consider resubmitting their safety request. Disclosures: No relevant conflicts of interest to declare.

Description: Immune checkpoint therapy has resulted in remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible SH2-containing (CIS) protein, a key negative regulator of interleukin (IL)-15 signaling, with fourth generation 'armored' chimeric antigen receptor (CAR-IL-15) engineering of cord blood (CB) derived natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell anti-tumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that targeting a cytokine checkpoint further enhances the antitumor activity of IL-15 secreting armored CAR-NK cells by promoting their metabolic fitness and anti-tumor activity. This combined approach represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.