Citations

Abstract Abstract 3708 Background: There are few prospective studies on disease characteristics, patterns of care, response, and outcomes in elderly FL patients (pts) in the US. The NLCS is a Genentech-sponsored prospective multicenter registry study that collects this information without study-specific treatment. We utilized the NLCS database to better understand the impact of age on FL outcome. Patients and Methods: All evaluable pts with FL histology in the NLCS were included except pts with FL plus other lymphoma histology or pts who progressed before first treatment or before being assigned to watchful waiting (WW). Using Pearson Chi-Square tests, associations of age groups (≤60, 61–70, >70) with disease characteristics and overall response (ORR) were examined. Median PFS and OS by treatment regimen were estimated using Kaplan-Meier methods for each age group. Cox proportional hazards regression adjusted for baseline factors (grade, number of nodal sites, LDH, Hgb, stage, performance status (PS), bone marrow (BM) involvement, race, and treatment center type) were used to assess treatment differences in PFS and OS and the significance of age by treatment interactions. Results: Of 2,647 pts, 47% (n=1,254) were ≤60 yrs, 25% (n=666) were 61–70 yrs, and 27% (n=727) were >70 yrs (min age of 22; max of 97). Compared with pts ≤60 yrs, pts 61–70 and >70 were more likely to be white (93% >70, 92% 61–70, and 88% ≤60, P=.02 and .02 respectively), have stage I/II disease (37% >70, 36% 61–70, and 29% ≤60, P=.0008 and .0003), have <5 nodal sites (73% >70, 69% 61–70, and 61% ≤60, P=.001 and <.0001), and have poor-risk FLIPI (53% >70, 51% 61–70, and 15% ≤60, P<.0001 and <.0001). Compared with pts ≤60, elderly pts (>70) were more likely to have FL grade 3 (24% vs 18%, P=.01). While there were no differences in geographic distribution by age, elderly pts were more likely to receive therapy at community practices (86%) versus academic institutions than pts ≤60 (77%, P<.0001) or 61–70 (81%, P=.004). Treatments varied significantly by age (P<.0001). More elderly pts were observed compared to pts ≤60 (23% vs19%). When treated, elderly pts (22%) were more likely to receive rituximab (R) monotherapy compared with patients aged 61–70 (12%) or ≤60 (10%). When chemotherapy alone or plus R was given, elderly pts were less likely to receive anthracyclines (45% vs 65% (61–70) and 68% (≤60)). Among all variables, only grade 3 histology predicted anthracycline use in all age groups. Lack of BM involvement predicted anthracycline use for younger pts (≤60 and 61–70). Of those ≤60, white pts were more likely to receive anthracyclines, and of those 61–70, those with ≥5 nodal sites were more likely to receive anthracyclines. ORRs were similar across age groups receiving similar regimens with R plus chemo providing the highest ORR. Adjusting for baseline factors, treatment (WW, R, R-Chemo, or other) benefit varied for each age group in terms of PFS (P=.02), with treatment outcomes being most differentiated among younger pts (Table). PFS appeared shorter in elderly pts regardless of the treatment received. No significant interaction between age and efficacy of anthracycline in terms of PFS or OS was observed (P-values >.65), but the overall effect of anthracycline for all pts was beneficial for PFS (HR=0.80, P=.02) and OS (HR=0.67, P=.003). Median OS was 8 years for elderly and not reached for others. After adjusting for baseline factors, no significant differences in treatment impact by age on OS were seen. Elevated LDH, reduced Hgb, stage III/IV, PS ≥1, and BM involvement were all significantly associated with shortened OS. These factors were also significantly associated with treatment choice, as worse-prognosis elderly pts were more likely to receive either R or R+chemo than WW or other treatment. Conclusions: FL pts >70 yrs more commonly received R alone and less commonly received anthracyclines when treated with chemotherapy. The impact of anthracyclines on PFS did not vary by age, but differences in PFS for other treatment regimens showed a stronger association among younger pts Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Byrtek:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Dawson:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Link:Genentech, Inc., a member of the Riche Group: Consultancy; Celgene: Consultancy; Spectrum: Consultancy. Friedberg:Genentech: Consultancy. Cerhan:Genentech: National LymphoCare Scientific Advisory Board Other. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy, Research Funding; Genentech: Consultancy; GIlead: Research Funding; Spectrum: Research Funding; Janssen: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees.

Abstract To date, whole genome and exome sequencing studies of follicular lymphoma (FL) have primarily focused on identification of small site mutations that are recurrent in FL tumorigenesis or involved in tumor clonal evolution. A comprehensive genomic and transcriptomic survey of various mutation types including large structural variants (SVs) in FL cases with detailed clinical annotations and long-term follow-up has not been accomplished. To gain insight into genetic biomarkers that may predict clinical features, we performed exome and whole genome mate-pair sequencing of fresh frozen tumor and paired peripheral blood DNAs, and transcriptome sequencing of tumor RNAs, from 8 FL patients. The patients we selected were either below the median age of FL onset (n=7, median 54.5 yrs) or had a family history of lymphoma (n=1). These patients were clinically diverse, and included patients who had Grade 1 or 2 disease (n=4), classified as “indolent”; and patients with Grade 3a disease (n=2) or who subsequently had pathologic transformation (n=2), classified as “aggressive”. The coding regions of the genome (exome) were captured using Agilent SureSelect Target Capture Kit V2.0, and sequenced at 100-bp paired-end. The single nucleotide variants (SNVs) and small insertions and deletions (INDELs) were called using The Genome Analysis Toolkit (GATK), and the exon level copy number variants (CNVs) we identified using patternCNV. The whole-genome mate-pair libraries of both normal and tumor DNAs with 3kb insert sizes were sequenced paired end at 50-bp. The large SVs of CNVs, large INDELs, translocations, and inversions were identified using the SnowShoes-SV algorithm. The RNA sequencing libraries of 8 FL tumors were constructed using Illumina TruSeq protocol, and sequenced at 50-bp paired end. The RNA-Seq data were analyzed using TopHat and the fusion transcripts were identified using SnowShoes-FTD. Our analysis of SNVs and INDELs revealed mutations in previously reported genes including MLL2, CREBBP, TNFRSF14, and histone cluster genes (HIST1H2AM, HIST1H2BD). In addition, we identified novel recurrent mutations in cysteine-rich PAK1 inhibitor (CRIPAK) in 25% of the tumors. In a secondary analysis performed by Sanger sequencing or re-analysis of publically available RNA sequencing data, we identified CRIPAK mutations in 44% of FL (n=32) and 28% of DLBCL tumors (n=102). Bioinformatics analysis shows that the coding region of CRIPAK is highly enriched with the protein functional domain, post-SET, which is usually found in histone lysine methyltransferases (HMTase) genes including MLL2 and EZH2 that are known to be important in lymphomagenesis. Interestingly, CRIPAK is part of the same regulatory network consisted of previously identified lymphoma genes including MLL2, EZH2, CREBBP, and EP300, according to the shortest path algorithm by MetaCore (Philadelphia, Pennsylvania). Recurrent SVs identified in the FL tumors included the well-known IGH-BCL2 translocation, or t(14;18), in 6 out of 8 cases (75%) and the chr1q amplifications in 4 out of 8 (50%) tumors. Other non-recurrent large CNVs involving entire chromosomes or chromosome arms, as well as other inter- and intra-chromosomal structural variants were detected in individual tumors. In addition, we identified and validated 6 fusion transcripts from the transcriptome sequencing data in 3 out of 8 cases (38%). While our sample size is small, we found that SNVs and INDELs in MLL2, CREBBP, TNFRSF14, CRIPAK, and histone cluster genes, as well as t(14;18), did not distinguish indolent or aggressive tumors. However, all aggressive (4/4, 100%) and none of the indolent tumors had gains in chr1q; and the presence of RNA fusion transcripts were observed in aggressive tumors only (3/4, 75%). Additionally, we found that aggressive tumors had higher numbers of genes with point mutations (SNVs and short INDELs) (40 ± 7.6 vs. 26 ± 2.6; aggressive vs. indolent), higher numbers of genes impacted by copy number aberrations (1060 ± 263.7 vs. 233 ± 133.9), and higher numbers of large SVs (24 ± 10 vs. 6 ± 1.6). Taken together, our comprehensive analysis of 8 FL tumors reveals genetic diversity among newly diagnosed FL patients, identifies novel and recurrent mutations in CRIPAK, and finds that high tumor complexity and DNA instability may be indicators of aggressive disease. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3701 Background: Salvage chemotherapy and autologous stem cell transplantation (ASCT) in the management of relapsed or refractory Hodgkin's lymphoma (HL) results in prolonged disease-free survival in only around 50% of patients (pts). Median survival following relapse from ASCT is estimated at 2.4 years, with poor outcomes in those experiencing relapse or progressive disease within one year from ASCT (Horning 2008 et al). Recently, a pivotal multicenter Phase 2 trial investigated the efficacy of brentuximab vedotin (BV) in pts with recurrent HL following ASCT. The study demonstrated an overall response rate of 75% and median duration of response of 6.7 months. Furthermore, 34% of patients achieved a complete response (CR), with a median progression free survival of 29 months (mos). Whether treatment with BV renders an OS benefit in pts with relapsed or refractory disease after ASCT remains to be determined. Objective: 1) To compare OS in pts with relapsed HL after receiving ASCT in a cohort of 102 HL pts treated with BV, with 756 pts from 6 international centers before the introduction of BV. 2) To evaluate predictors of durable CR in pts treated with BV. Methods: Kaplan-Meier method was used to depict time-to-event outcomes, including OS. The Chi-square test was used to evaluate the association between two categorical variables and log-rank test to compare time-to-event endpoints among pt groups. Based on the univariate proportional hazard model, we examined whether certain variables (sex, stage at diagnosis, number of prior treatments, and time to CR) were predictors of CR duration in pts receiving BV. Results: In the non-randomized comparison between those with relapsed-refractory HL following ASCT who received BV and those who did not, pts were well matched by age, with a relatively higher percentage of females treated on the pivotal study. Dates of progression from ASCT ranged from 1996–2009 in the BV group and 1981–2003 in the international cohort. Median follow-up after ASCT for the censored observations of pts who received BV and those in the international cohort was 49.4 and 58.8 mos. The difference in median OS was statistically significant (p<0.0001) between those receiving BV and those not exposed to the drug (91.49 vs. 27.99 mos). Improvement in OS was irrespective of time to relapse from ASCT, despite previous studies noting a higher risk of recurrence in pts relapsing within 12 mos of ASCT (Sureda 2005 et al). Neither age nor sex was found to impact OS. In the subgroup analysis of pts achieving a CR with BV, univariate analysis of duration of CR and PFS uncovered no significant factors, while only stage of disease at initial diagnosis had a significant effect on OS (P=0.0004). Disease status characterized as relapsed vs. refractory had borderline significance with a positive impact on OS (P=0.0581). No significant associations were noted between the variables and duration of response post BV stratified into periods of less or greater than 12 mos. However, among those pts who experienced a duration of CR greater than 12 mos, 81.8% (n=18) had an initial CR after receiving ≤ 4 doses of BV, compared with 58.3% entering CR after receiving > 4 doses. Conclusions: While the impact of BV on OS can only be determined through a randomized clinical trial, our analysis indicated that treatment with BV in pts with relapsed/refractory HL following ASCT is associated with prolonged OS when compared with historical control patients. Those who achieve a rapid CR with BV may also have a longer duration of response. A randomized clinical trial is ongoing to evaluate prospectively the efficacy of BV following ASCT. Disclosures: Chen: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau. Gopal:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding; Celgene: Consultancy. Savage:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Ramchandren:Seattle Genetics, Inc.: Speakers Bureau. Forero-Torres:Seattle Genetics: Research Funding. Moskowitz:Seattle Genetics: Speakers Bureau. Connors:Seattle Genetics, Inc.: Research Funding. de Vos:Seattle Genetics: Speakers Bureau. Engert:Takeda: Honoraria, Research Funding; Millennium: Honoraria, Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Morschhauser:Takeda: Honoraria. Younes:Seattle Genetics: Honoraria.

Abstract Abstract 4931 Background: Autoimmunity, evidenced by positive serology or autoimmune diseases, has been noted to co-exist in pts with MDS. Autoimmune dysfunction has been found in some pts with a variant of MDS called hypocellular MDS, where immune suppressant medications have role in treatment. Clinical implications of AI on survival are not well described. Aim: To study clinical influence of autoimmunity on pts with LR-MDS. Methods: All adult pts diagnosed with LR (RCUD, RARS, and RCMD) MDS at the Mayo Clinic between 1996 to 2000 were studied. Retrospective data collection included pts' demographics, laboratory tests, bone marrow biopsies, treatment modalities and survival information. Autoimmunity (AI) was considered present if pts had evidence of positive serological testing (such as rheumatoid factor (RF), anti-nuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA)) and/or were diagnosed with autoimmune diseases (such as rheumatoid arthritis, vasculitis, autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP)). IRB approval was obtained in accordance with Helsinki Declaration. Chi-Square, t-test and Anova were used for comparatives between groups, and Kaplan-Meier test was applied for survival estimates using JMP 9. 0 software. Results: A total of 134 adult pts were found to have LR-MDS at the time of their diagnosis. Sixty-six percent (89) were males, 13% (17) had antecedent hematological disease (AHD), and only 7% (9) had prior radio- or chemotherapy. Thirty-nine (29%) had evidence of AI. At the time of diagnosis, pts' median Hgb was 9. 3 g/dL, white blood cells (WBC) 4. 1×109/L, and platelets 151×109/L. On comparison, there was no difference between pts with AI (group 1) to the rest of the sample (group 2) (p = 0. 12, 0. 85 and 0. 23, respectively). Bone marrow cytogenetics were abnormal in 42% (56) pts, with 44 pts have one cytological anomaly, and only 2 have four anomalies. Twenty-four pts (18%) had RCUD, 60 (44%) RARS and 50 (37%) RCMD, as defined by World Health Organization (WHO) classification (Vardiman et al, 2008). Karyotype anomalies within the three WHO classes were found in 12/19 pts (63%), 15/52 pts (29%), and in 29/42 pts (70%), respectively. Of note, among those with karyotype anomalies, the mean number of cytogenetic abnormalities was significantly different across the three categories (F=6. 89, p=. 0014), with means of 0. 5, 0. 3, and 0. 9 respectively. Seven pts (5%) progressed into acute myeloid leukemia. Seventy percent of pts (94) remained as stable disease. Of the 134 pts studied, 39 (29%) were found to have evidence of AI, with 24/48 (50%) had abnormal serological tests, and 29/134 (21%) had an autoimmune disease. When tested, positive RF was found in 7/25 (28%), ANA in 14/42 (33%), anti dsDNA in 1/11 (9%), anti SS-A/-B in 2/3 (66%), ANCA in 1/12 (8%), anti-smooth muscle in 1/2 (50%), and anti-histone in 1 pt. As per autoimmune diseases, rheumatoid arthritis was identified in 6 pts (4%), vasculitides in 9 (7%), AIHA in 4 pts (3%), Sjögren syndrome in 3 (2%), myositis in 2 (1. 4%), ITP in 2 pts (1. 4%). There was no difference in AI frequency based on WHO classification (p 0. 17) or based on cytogenetic grouping (p 0. 37). Overall survival in pts with LR-MDS was found to be lower in group 1 as compared to group 2 but did not reach statistical significance (p=0. 109), with median survival of 40 months and 81 months, respectively. Conclusion: AI is a frequent finding in pts with LR-MDS, seen in up to 29% of pts. On comparison there was no difference in hematological parameters of both groups with or without AI (CBC, cytogenetics, and WHO classification). There was no survival difference in LR-MDS pts with AI compared to pts without AI. Larger size studies are needed to confirm our findings. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4930 Background: Autoimmune disorders have been observed in pts with myeloid neoplasms but their frequency and impact on the natural history of the myeloid neoplasms remains to be defined. Aim: To describe the frequency and prognostic impact of autoimmunity in pts with CMML. Methods: After IRB approval, a retrospective chart review of all pts diagnosed with CMML at Mayo Clinic between 1994 – 2011. Autoimmunity (AI) was defined as positive serologic tests (Anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti –cyclic citrullinate peptide (CCP), and antineutrophil cytoplasmic antibodies (ANCA)), diagnosis of connective tissue disease (Rheumatoid arthritis, RA), vasculitis, or auto-immune thrombocytopenia (ITP). Survival estimates were calculated using Kaplan-Meier estimates and Cox regression model for multivariate analysis for via JMP software v. 9. Results: During the study period, 288 pts with CMML were evaluated at Mayo Clinic, 35% (n=100) were female. Median age at diagnosis was 71yr (20–95). Median hemoglobin was 11 g/dL(6–16), median white blood cell (WBC) 12 x109/L (1–302), and median platelet count 86 x109/L (1–1110). Median peripheral blood (PB) and bone marrow (BM) blasts were 0 and 5 respectively, while median PB and BM monocytes were 20% and 8% respectively. Eight-nine percent of pts had CMML1, while 10% had CMML2 and only 2 pts had CMML transforming into acute myeloid leukemia (-t). Karyotype analysis performed in demonstrated normal (diploid) karyotype in 180 (63%) pts and complex karyotype in 31 pts (11%). JAK2 mutation analysis was performed in 76 pts, 13% (10/76) of which were positive for JAK2V617F mutation. Autoimmunity was found in 46 (16%) of 288 pts. When tested, positive ANA, RF, CCP, and ANCA were found in 28/89 (31%), 8/61 (13%), 1/20 (5%), and 7/25 (28%), respectively. However, RA was reported positive in 6/288 (2%), and vasculitis was reported in only 4 pts. Median overall survival of the 288 patients was 496 days. Pts with evidence of autoimmunity had a median survival of 400 days compared to 527 days to the rest of the group (p 0. 73). On multivariate analysis, autoimmunity was not an independent risk factor for survival (p 0. 15), but age, platelets, WBC and body mass index (BMI) were independent factors. Conclusion: Autoimmunity is a frequent finding in pts with CMML. When tested, autoimmune antibodies were very frequent up to 31% of pts with CMML, but this did not confer into higher frequency of autoimmune diseases. Presence of positive autoimmune antibodies did not affect overall survival adversely. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3841 Introduction: The International Prognostic Scoring System (IPSS) has recently been revised (IPSS-R) to capture more inclusive cytogenetic characterization, more stringent blast description, and more detailed cytopenia assignments. To validate the IPSS-R in a prospective cohort of patients, we compared IPSS and IPSS-R categorization within a group of newly diagnosed MDS patients in a prospective population-based epidemiologic study in Minnesota. Methods: We identified all newly diagnosed MDS cases in Minnesota between the ages of 20 and 85 years from April 1, 2010 to April 2012. Our process includes rapid case identification by the Minnesota Cancer Surveillance System (MCSS), patient contact and enrollment, central medical review including: 1) independent review by two hematopathologists to confirm diagnosis and WHO subclassification; 2) independent cytogeneticist's review for classification as defined by IPSS and IPSS-R; and 3) medical chart review with prospective calculation of IPSS, IPSS-R, and WPSS by a an oncologist. Results: Classification of the 128 patients by IPSS versus IPSS-R is shown (Table) Kendall's Tau = 0.77 In this comparative classification, IPSS-R scoring refined the MDS prognostic risk groups. Low IPSS remained low risk in the IPSS-R spanning the Very Low and Low groups, while all high risk IPSS remained in the Very High risk group in the IPSS-R. However, those in the INT-1 and INT-2 IPSS categories were inconsistently reclassified in the IPSS-R. INT-1 IPSS spanned from Very Low to High and INT-2 IPSS spanned from Intermediate to Very High in the IPSS-R. While reclassification of this prospective cohort resembles results in the IPSS-R reports, ongoing follow-up will be needed to determine if the survival and AML progression measures are reproducible. Conclusion: Until molecular data are available to refine future prognostic scoring systems, the IPSS-R enhances our prognostic risk stratification abilities and is applicable to the general MDS population. As treatment decisions are based on this initial prognostic risk assessment, the more diverse differentiation of risk within the IPSS-R will directly refine prognosis and impact decisions on therapy. Disclosures: Miller: Celgene: Membership on an entity's Board of Directors or advisory committees; Coronado Bioscience: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 1851 Background: In previous work we performed RNAi sensitizer screening of epigenetic modulation with 5-Azacytidine and the human kinome. Few kinase hits were identified. Therefore we asked if phosphatases might be involved in modulating epigenetic therapies. Thus in order to identify potentiators of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) we performed high-throughput RNA-interference (RNAi) lethality screening using the myeloid cell lines HEL, THP-1 and TF-1 in combination with SAHA. Methods: A small-interfering RNA (siRNA) library targeting 206 phosphatases with 4 sequences per target gene was used for this study. siRNA were transfected in a single-siRNA-per-well format in 384-well plates using commercial lipid-based transfection reagents. Non-silencing siRNA were included as negative controls to access non-specific siRNA toxicity and universal lethal siRNA were included as positive controls to indirectly assess functional transfection efficiency. After a 96 hour incubation period, cell viability/proliferation was measured with Cell Titer Glo. For analysis of screen data, log2 values of (SAHA + siRNA treatment/siRNA treatment only) were calculated. Potentiation was defined as two standard deviations from the median log2 ratio of all siRNA (excluding positive controls) on a plate-by-plate basis. Hits were defined as ≥ 2/4 siRNA sequences meeting potentiation criteria. Results: Transfection efficiency was 95, 90 and 70% for HEL, THP-1 and TF-1, respectively. All three cell lines were similarly sensitive to SAHA with IC50 values of 0.3, 0.4 and 0.6 μM for HEL, THP-1 and TF-1, respectively. Resulting SAHA concentrations for screens were between the IC5 to IC30. For THP-1, 5 phosphatases qualified according to the hit selection criteria applied indicating strong potentiation to SAHA. Of these 5 hits, 3 did not exhibit strong reductions in viability with siRNA alone, suggesting a SAHA-dependent relationship. For HEL and TF-1, although no phosphatases met the strict selection cutoff, there were several phosphatases exhibiting potentiation, suggesting biological relevance. The primary screening data and preliminary analysis will be validated with rigorous secondary experimentation and top hits for all cell lines will be investigated and advanced. Conclusions: While there are numerous kinase inhibitors in the clinic and in preclinical development, phosphatases are much less explored as therapeutic targets. Validated potentiating targets from this RNAi screen can facilitate the development of rational SAHA combination therapies. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3702 Background: Both drug choice and delivered dose of intended treatment potentially influence outcome in patients treated for follicular lymphoma (FL). Historically, observational studies have solely evaluated drug choice. The National LymphoCare Study (NLCS) is a prospective, observational study that enrolled >2700 patients with FL in the United States between 2004 and 2007. We report on measures of delivered dose and its impact on outcomes for the most common first-line regimens. Methods: All evaluable patients treated with R-CHOP, R-CVP, or R-fludarabine (R-Flu)–containing regimens in the NLCS were included, except those with FL plus other lymphoma histology, non-FL histology, or those who progressed before first treatment or before being assigned to watchful waiting. Associations between baseline factors and choice of treatment (R-CHOP, R-CVP, or R- Flu–containing regimen), number of cycles received (≤4, 5–6, 7+), and completion of therapy were assessed using the Pearson chi-square test. Factors associated with risk of early discontinuation were assessed using logistic regression, and a generalized logits model was used to assess the relationship between baseline factors and number of cycles received. Kaplan-Meier methods and the log-rank test were used to estimate progression-free survival (PFS), overall survival (OS), and time to next treatment. Results: Among 1165 evaluable patients, a total of 648 received R-CHOP, 296 received R-CVP, and 221 received R-Flu combinations. Patient characteristics were similar between groups with the following exceptions: patients receiving R-CHOP were more likely to have grade 3 FL (38% vs 11% for R-CVP and 13% for R-Flu), and patients receiving R-CVP were older (25% ≥75 vs 8% for R-CHOP and 13% for R-Flu) and had higher Follicular Lymphoma International Prognostic Index (FLIPI) risk scores (50% poor FLIPI vs 41% for R-CHOP and 36% for R-Flu). The distribution of delivered cycles demonstrated a high degree of compliance with published regimens, with most patients receiving ≥5 cycles of treatment (R-CHOP 86%, R-CVP 81%, R- Flu 67%, P<.0001). The median cycle length was 21 days for both R-CHOP and R-CVP, and 29 days for the R-Flu regimens. Cycle intensity, defined as the expected cycle length (21 days for R-CHOP and R-CVP, and 28 days for R-Flu) divided by the actual cycle length, was between 0.9 and 1.1 for 68% of R-CHOP patients, 75% of R-CVP patients, and 45% of R-Flu patients. The percentage of patients with longer-than-expected time between cycles (cycle intensity <0.9) was similar for the 3 treatment groups; however, R-Flu patients were more likely to have shorter-than-expected time between cycles (24% vs 4% for R-CHOP and 3% for R-CVP). We sought to understand the reasons for patients receiving ≤4 cycles. Most patients who received ≤4 cycles were considered to have completed the intended duration of therapy (58% for R-CHOP, 62% R-CVP, and 75% R-Flu); rates of early discontinuation from the intended treatment were significantly less for patients receiving ≥5 cycles. Early discontinuation was associated with age ≥75 years and treatment with R-Flu (particularly in patients with grade 1–2 FL). Toxicity was the most commonly cited reason for early discontinuation (47% for R-CHOP, 46% for R-CVP, and 71% for R-Flu). The higher rate of R-Flu discontinuation due to toxicity is consistent with findings from other studies. Disease progression was rarely cited as the reason for early discontinuation. Time to retreatment was significantly shorter for patients receiving ≤4 cycles for patients receiving R-CHOP and R-CVP compared with patients receiving 5–6 cycles and 7+ cycles (P=.002 and P<.001 respectively; medians not yet reached). Delivery of ≤4 treatment cycles was associated with lower response rates (76% CR/PR vs 90% for 5–6 cycles and 92% for 7+ cycles) and worse PFS and OS, among patients who received R-CVP (all P<.01) but not among other regimens. Conclusions: Most patients with FL receiving chemoimmunotherapy in the NLCS completed ≥5 cycles of treatment. Most who received fewer cycles were considered to have completed therapy, and therapy commonly was given at or above the expected cycle intensity. Strategies to improve dose delivery appear unlikely to impact patient outcomes, except possibly in patients receiving R-CVP. Disclosures: Martin: Genentech: Speakers Bureau. Link:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrtek:Genentech: Employment. Dawson:Genentech, A Member of the Roche Group: Employment. Friedberg:Genentech: Membership on an entity's Board of Directors or advisory committees. Cerhan:Genentech: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 47 Background In adults with newly diagnosed, poor-risk AML we previously demonstrated that induction therapy with Flavopiridol in combination with Ara-C and Mitoxantrone (FLAM,) in a timed-sequential manner, yields complete remission (CR) rates of 67% and median disease-free survival (DFS) of 13.6 months. These data suggest that FLAM might improve outcomes relative to standard “7+3” in newly diagnosed AML with poor-risk features. Thus, we are conducting a phase II randomized trial comparing the CR rates with FLAM vs. 7+3 induction for all newly diagnosed adult patients with AML with intermediate and poor-risk features. We also previously identified a population of CD34+CD38− cells with intermediate aldehyde dehydrogenase (ALDH) activity that appears to represent a leukemic stem cell (LSC) population. We are examining the effects of FLAM vs. 7+3 in eradicating this LSC population and determining if persistence of LSC's predicts for relapse. Objectives The primary objective is to compare the rate of CR after 1 cycle of FLAM vs. 1 cycle of 7+3. The secondary objectives are to compare toxicities, survival rates, and presence or absence of minimal residual disease (MRD) after both induction regimens. Methods All newly diagnosed adult patients aged 18–70 without favorable risk features were randomized in a 2:1 fashion between FLAM and 7+3 at 90 mg/m2 of Daunorubicin. To achieve balanced randomization, patients were stratified by age, secondary AML and leukocyte count. CD34+ cell subsets were analyzed by flow cytometry for CD38 expression and ALDH activity by Aldefluor. The trial is ongoing. Results To date, 62 patients are evaluable for the primary end point. Demographics and results are depicted in table 1. Patient characteristics were similar in both arms, although there were more patients with poor risk features in the FLAM arm than 7+3. Overall grade > 3 toxicity was similar between both arms. However, there were 3 cases of grade > 3 tumor lysis syndrome (TLS) with FLAM, with 1 death, vs. 0 with 7+3. There were also 3 deaths with FLAM before day 60 vs. 0 with 7+3. CR rate with FLAM was 68% (28/41), with 1 cycle of 7+3 was 48% (10/21) (p = 0.17), and with 2 cycles (7+3 + 5+2) was 52% (11/21). CR rates based on specific risk factors are depicted in table 2. There was a trend toward improved CR rates in patients with adverse genetics with FLAM (p = 0.17). Putative AML LSC's were distinguished from normal hematopoietic stem cells based on ALDH activity. The persistence of putative LSC's in patients after therapy was highly predictive of subsequent clinical relapse. Conclusions Based on the current CR rate of 68%, FLAM holds promise as a therapeutic option for patients with newly diagnosed AML with intermediate and poor risk features. In this preliminary analysis, there is a suggestion that FLAM leads to higher CR rates in patients with adverse genetics than 7+3. Additionally, the detection of MRD consisting of a residual putative LSC population strongly portended subsequent relapse, even in patients without evidence of leukemia. Disclosures: Off Label Use: Flavopiridol (Alvocidib) is an anti-leukemia agent.

Background: Anaplastic thyroid cancer (ATC) has poor prognosis with median overall survival (OS) of ∼6 months. We previously reported high PD-1/PDL-1 staining in ATC, raising the possibility of the productive application of the immunotherapeutic pembrolizumab. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. Methods: An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 2 each IV weekly plus volumetric modulated arc therapy) was initiated as frontline therapy (with or without surgery) in ATC to assess efficacy and toxicities. Six-month OS was selected as the primary endpoint using a Simon's optimal design with interim analysis (targeting accrual of 25 patients; Cohort A: prior resection, Cohort B: no resection). Based on a prior patient cohort-treated similarly, but without pembrolizumab, the design was such that, if 6-month true survival is 75%, the probability of declaring the approach worthy of further pursuit would be 91%. Results: Three patients were enrolled, two with rapidly enlarging unresectable neck masses. Early tumor responses were favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation—one from pulmonary metastases and two from otherwise unexpected fatal pulmonary complications occurring subsequent to chemoradiotherapy completion—prompting study closure. Conclusions: Although initially tolerated and effective in terms of locoregional disease control, disappointing survival outcomes compared with historical controls raise uncertainty that the piloted approach merits further pursuit in ATC.