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Abstract Abstract 149 Background. There are few established factors that predict risk of follicular lymphoma (FL) transformation, and only two studies have evaluated the role of germline genetic variation and risk of transformation. One study reported an association of a BCL6 SNP (397C>G) with risk of transformation, and a second study reported an association with rs6457327, which is in the HLA region of 6p21. This study evaluated the risk of FL transformation in the modern treatment era with germline SNPs that were previously reported to be associated with FL transformation (BCL6SNPs and rs6457327), along with SNPs (N=45) previously associated with either risk of FL or FL prognosis. Methods. Newly diagnosed FL patients were prospectively enrolled from 2002–2009 into the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma SPORE. Peripheral blood for genotyping was collected at enrollment, and clinical and treatment data were abstracted from medical records. All patients were actively followed for disease progression, retreatment, transformation and death. For this analysis, only FL patients with grade I-IIIa were included. Patients with composite DLBCL, FL grade IIIb, or other evidence of transformation at diagnosis were excluded. Transformation was based on either 1) biopsy confirmation of FL grade IIIb, DLBCL, or higher grade B-cell lymphoma; or 2) clinical indicators of transformation based on the published literature, including sudden rise in LDH, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B-symptoms, or hypercalcemia. Genotyping was conducted using a custom Illumina iSelect panel. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with time to transformation, with death modeled as a competing risk. Each SNP was modeled with the most prevalent homozygous genotype used as the reference group, and each SNP was modeled as having a log-additive (per minor allele) effect in the regression model. An ordinal test was used to assess the trend, and p<0.05 was considered statistically significant. Results. There were 631 newly diagnosed grade I-IIIa FL patients, of whom 532 had DNA and were successfully genotyped. The median age at diagnosis was 60 years (range 23–93) and 53% were male. FLIPI distribution was 42% 0–1, 34% 2 and 24% 3–5. Initial therapies included observation (32%), rituximab (R) monotherapy (13%), alkylator-based chemotherapy +/− R (20%), and anthracycline-based chemotherapy +/− R (19%). At a median of 59 months of follow-up (range, 11–110), 58 patients died, 254 had an event (death, progression or retreatment) and 54 patients (10%) transformed. Transformation was biopsy proven in 43 of the 54 patients (80%). The SNP rs6457327 on chromosome 6p that was previously reported to be associated with transformation was positively associated with risk of transformation in our data (HR=1.40; 95%CI 0.97–2.04; p=0.07), although this association was weaker but still consistent with the prior report. Further, we evaluated additional typed SNPs from the HLA region of 6p, and found additional associations (p<0.05) with HLA-DRA (3 SNPs), HLA-DQA2 (2 SNPs), HLA-DOA (2 SNPs) and HLA-DPB1/HLA-DPA2 (2 SNPs), of which rs10484569 from HLA-DPB1/HLA-DPA2 was the most strongly associated with risk of transformation (HR=3.01; 95%CI 1.48–6.09; p=0.002). None of the BCL6 or other previously reported risk SNPs were associated with transformation. Of the SNPs previously associated with FL prognosis, only the FCGR2A rs1801274 (HR=1.41; 95%CI 0.94–2.10; p=0.09) and CD46 (CD46 molecule, complement regulatory protein) rs2466571 (HR=1.72; 95%CI 1.16–2.55; p=0.007) were associated with risk of transformation. For CD46, one additional SNP (rs2796269) was also associated with transformation (HR=0.61; 95%CI 0.40–0.95; p=0.03). Further adjustment for FLIPI score and treatment (observation versus all other) did not alter these associations. Conclusions. The previously reported association of rs6457327 with risk of transformation in the modern treatment era was replicated. In addition, several HLA loci and two FL prognosis SNPs were linked to transformation risk. The remaining published FL risk or prognosis SNPs were not associated with transformation. Our results support a role for germline genetic variation in the HLA region, FCRGR2A and CD46 in transformation of FL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1525 Background: Nodular lymphocyte predominant Hodgkin Lymphoma (NLPHL) is a more indolent form of Hodgkin Lymphoma that is usually associated with favorable outcomes. However, a number of reports have shown a tendency of transformation to more aggressive types of lymphoma, typically diffuse large B-cell lymphoma (DLBCL). Long-term data on the incidence and outcomes of transformed NLPHL is lacking in the literature. The aim of this study was to evaluate incidence, risk factors and outcomes of DLBCL transformation in NLPHL in a cohort of patients followed at a single institution. Methods: The actively maintained Mayo Clinic Lymphoma Database includes all consenting consecutive patients with lymphoma seen at Mayo Clinic Rochester. This was used to retrospectively identify patients with NLPHL. The study was approved by the Institutional Review Board. Pathology was reviewed by a hematopathologist and all transformations were histologically confirmed by WHO criteria. The clinical characteristics, therapy and outcomes of patients with NLPHL and DLBCL transformation were analyzed. The chi-square test was used to compare variables. Risk of progression was calculated using a person-year approach. Survival and freedom from transformation were estimated and compared using the Kaplan Meier method and log rank tests, respectively. Results: Between 1970 and 2010, 222 consecutive adult patients with NLPHL were identified. The median follow-up was 20 years. Of these, 17 (7.7%) developed a transformation to DLBCL during the course of the disease (Figure 1). The median time to transformation was 35 (6–248) months. Of these 17 patients, 13 (76.5%) were male, 11 (64.7%) had stage I/II and 6 (35.3%) had stage III/IV NLPHL. Transformation was the first relapse in most patients (12 patients, 70.6%) while five patients (29.4%) developed one or more relapses of NLPHL before transformation. Prior therapies for NLPHL were as follows: radiation therapy in 5 (29.4%), chemotherapy in 5 (29.4%) and combined chemotherapy and radiation in 6 (35.3%) patients. The median age at transformation was 45 years (30–87). Most patients (10 patients, 58.8%) presented with signs (palpable lymph nodes) or “B” symptoms. Eight patients (47.1%) had stage III/IV disease at the time of transformation. The most commonly used regimens for treatment of DLBCL were R-CHOP or CHOP (9 patients, 52.9%). Platinum based therapy was administered in 4 (23.5%) patients. Five patients (29.4%) required more than one line of therapy, and autologous stem cell transplant was utilized in two (11.7%) patients. Based on the observed 17 transformations during 2304 patient-years of follow-up, the rate of transformation was 0.74 per 100 patient-years. The five-year overall survival (OS) of patients with transformed disease (calculated from time of transformation) was 76.4%. The most common cause of death was lymphoma (75%). Following treatment for transformation, 5 patients (29.4%) relapsed. The OS in transformed patients was independent of prior therapies, and transformation did not adversely affect overall survival in our cohort (median survival of in 129 months in transformed versus 120 in non-transformed patients, P=0.33). In a univariate analysis of prior therapies, use of radiation therapy was associated with a significant delay in time to transformation (P= 0.0035) (Table 1, figure 2). Conclusions: The risk of transformation in NLPHL is 0.74% per year in this large single institution case series of NLPHL, and appears to be lower than that observed in follicular and other types of low grade lymphoma. The outcomes of patients with transformation were significantly better than reported in other types of transformed lymphoma and did not adversely affect OS. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1563 Intro: Optimal treatment for non-follicular low grade B-cell lymphoma (NFLGL) is not well defined. Clinical trial design for these subtypes would be enhanced by further understanding of early presentation and management. A large prospective observational study was used to identify presenting clinical features, describe patterns of care and compare the prognostic utility of International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI). Methods: The University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) is a prospective, longitudinal observational study designed to collect information on patterns of care and outcomes for patients with newly diagnosed lymphoma. Patients seen at the Mayo Clinic, Rochester MN and the University of Iowa within 9 months of their initial diagnosis of lymphoma are offered enrollment. Baseline patient reported data, clinical data and initial management are collected using a standard protocol and a central pathology review is performed. After enrollment, patients are actively followed for events (disease progression, retreatment, and death) and disease related comorbidities. This analysis includes 198 patients diagnosed with extranodal marginal zone (EMZL), 22 with nodal marginal zone (NMZL), 47 with splenic marginal zone (SMZL), 48 with lymphoplasmacytic lymphoma (LPL), as well as 67 patients with unclassifiable low-grade B-cell lymphoma (B-NOS). Results: 382 newly diagnosed NFLGBL patients were enrolled in the MER from 2002–2009. The median age at enrollment was 63 years (range 22–95). 52% were male. The most common types of initial therapy after diagnosis were observation (41 %), alkylator- based chemotherapy +/− rituximab (R) (17%), radiation therapy alone (15%) and R monotherapy (13%). At median follow-up of 60 months (range 1–121), 51 patients were deceased and 155 had an event. The clinical characteristics that comprise the IPI and FLIPI were similar across the subtypes. Approximately half of the cases presented at low risk (55% IPI; 48% FLIPI). A majority had a normal LDH (81%), limited nodal involvement (91% had ≤ 4 groups), normal hemoglobin (71% ≥12 g/dL), good performance status (95% 0–1), and advanced stage (57% stages III-IV). There were notable differences among the NFLGBL subtypes. Patients with SMZL and LPL presented with high risk FLIPI of 3–5 (49% and 46% respectively) and high to high-intermediate IPI of 3–5 (21% and 13%). Abnormal LDH and anemia (< 12 g/dL) were more frequent in patients with SMZL (40%; 56%) and LPL (25%; 62%). EMZL presented with lower stages (70% stage I-II) and NMZL presented with increased nodal involvement (38% >4 sites). SMZL had the highest rates of surgical resection (21%) and EMZL was more frequently treated with radiation therapy (25%). LPL (30%) and NMZL (32%) more commonly received alkylator based chemotherapy +/− R. While both IPI and FLIPI differentiated outcome in these patients, FLIPI had higher c-statistics than IPI for both EFS (0.583 vs 0.568) and OS (0.685 vs 0.661), respectively. Conclusions: This large prospective collection of data on NFLGBL patients presenting to academic medical centers provides a modern picture of presentation and management patterns useful to investigators designing clinical trials. FLIPI may have more prognostic utility than IPI in this group of patients. Disclosures: Ansell: Seattle Genetics, Inc.: Research Funding.

Abstract Background Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL) with heterogeneous outcomes and remains largely incurable. Immunochemotherapy (IC) continues to be the standard therapy backbone in the frontline and relapsed settings, though novel agents are increasingly used and investigated. Lenalidomide is an immunomodulatory molecule with known single-agent activity in relapsed lymphoma. It is also active in the frontline setting and has been reported to be effective and tolerated in upfront combination regimens in FL (Fowler et al, Lancet Oncol. 2014, 15(12):1311-8). Here we report our experience with frontline use of R2CHOP (lenalidomide in combination with R-CHOP) in patients with FL. Methods A phase 1/2 study of R2CHOP was conducted in NHL patients with primarily diffuse large B-cell lymphoma (DLBCL). While the phase 2 study was focused on DLBCL patients, treatment-naive patients with stage II-IV, histologically-confirmed FL (grades 1, 2, and 3a) meeting criteria for therapy were eligible for the phase 1 part of the study. Additionally, FL patients were identified in the phase 2 portion of the study after central pathology review. These patients were allowed to complete therapy and were followed accordingly. Treatment consisted of 6 cycles of R2CHOP with lenalidomide given on days 1-10 and R-CHOP given in 21-day cycles. All patients received pegfilgrastim and aspirin (if not on anticoagulation) along with other supportive measures per provider discretion. Primary objectives were safety assessment and efficacy. Results Ten patients with FL (3 had grade 1, 3 had grade 2, and 4 had grade 3a) were enrolled in the R2CHOP phase 1/2 study at Mayo Clinic. One patient was in the phase 1 arm at dose level 2 (lenalidomide 20 mg/d) and 9 patients were in the phase 2 arm (lenalidomide 25 mg/d). The mean age was 60.8 years (range: 41-82). Eight out of ten patients were male; 5/10 had ECOG performance status of 0; 5/10 had an IPI score of intermediate or higher. All patients completed 6 cycles of planned treatment. One patient required lenalidomide dose adjustment due to toxicity. There were no lenalidomide dose interruptions. The overall response rate (ORR) was 100% and the complete response (CR) rate defined by PET imaging was 90%. Eight out of ten remain progression-free and 9/10 are alive at a median follow-up of 4.6 years (range: 2.1-5.3). Estimated progression-free survival (PFS) at 5 years was 79% (95% CI: 56-100%). The main toxicity was reversible myelosuppression with 80% treatment-related hematologic grade 3 or higher adverse events (AEs) (leukopenia 80%, neutropenia 80%, thrombocytopenia 40%, anemia 20%, transaminitis 20%). Rate of nonhematologic grade 3 or higher AEs was 20% (fatigue 10%, pneumonia 10%). Conclusions Frontline therapy with R2CHOP in patients with untreated FL appears to be effective and associated with acceptable toxicity. The observed PET-based CR rate and PFS were promising in this cohort. Whether R2CHOP is superior to lenalidomide/rituximab alone or standard bendamustine/rituximab will require randomized studies. Figure Estimated PFS in FL patients treated with upfront R2CHOP. Figure. Estimated PFS in FL patients treated with upfront R2CHOP. Disclosures Reeder: Celgene: Research Funding; Novartis: Research Funding; BMS: Research Funding; Millennium: Research Funding. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; karyopharm: Honoraria; medscape: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Nowakowski:Bayer: Consultancy, Research Funding; Morphosys: Research Funding; Celgene: Research Funding.

Abstract Background: Smudge cells are ruptured CLL cells seen on blood smears of CLL patients. For over a century, smudge cells were thought to represent an artifact of slide preparation. We recently showed that smudge cell formation was inversely proportional to leukemic B cell vimentin content. Vimentin is a cytoskeletal protein critical for lymphocyte rigidity and migration; high vimentin content is related to poor prognosis in CLL. Concordantly, in an initial small cohort of patients from a single institution, we found that patients with a low (<30%) percentage of smudge cells on a blood smear have a shorter time to treatment (Mayo Clin Proc.2007;82:449–53). In the current study, we evaluated the impact of smudge cell percentage on prognosis of patients with CLL seen at member institutions of the CLL Research Consortium (CRC). Methods: Archived blood smears from untreated patients with CLL were evaluated for smudge levels. All blood smears were prepared manually in a standard fashion from blood obtained by CRC Tissue Core and stained with WrightGiemsa stain. Smudge cells were defined as broken cells with no intact cytoplasm and a disrupted nuclear membrane. A total of 200 lymphocytes and smudge cells were counted on each slide and the results were expressed as the percent smudge cells. The association between the percentage of smudge cells, prognostic factors (IgVH status, CD38, ZAP-70 and FISH) and time to initial therapy (TTT) was examined. Results: We calculated smudge cell percentage on blood smears obtained prior to treatment for 337 CLL patients. The median smudge cell percentage was 32 (range 2–95%). The percentage of smudge cells was lower in CD38 positive patients (mean 33% vs. 38% in CD38 negative patients, p=0.04). No difference in smudge cell percentage was observed based on IgVH gene mutation status or Zap70 expression. Smudge cell percentage as a continuous variable was associated with prolonged TTT, exponential coefficient 0.98, p=0.04. Using our previously published cutoff of 30% to stratify patients in low and high risk categories, the estimated median time to first therapy of patients with smudge cell percentage ≤30% (n=178) was 7.8 years versus not reached in patients in patients with > 30% (n=159) of smudge cells, p=0.0036, (Figure 1). Ten years from diagnosis, 62% of patients with ≤30% of smudge cells versus 39% of patients with >30% of smudge cells required therapy. In multivariate analysis, the low percentage of smudge cells (≤30%) was an independent predictor of the shortened time to treatment (HR 1.86, 95%CI 1.09–3.16, p=0.02). Conclusion: This multicenter study confirms our initial finding that the percentage of smudge cells on a blood smear is an independent predictor of clinical outcome in patients with CLL. The estimation of smudge cell percentage on routine blood smear provides a simple and inexpensive prognostic test available to nearly all patients with a diagnosis of CLL worldwide. It also allows reanalysis and risk stratification of previously completed trials provided that blood smears have been archived. Further studies of the role of the cytoskeleton in CLL biology are warranted and ongoing in our laboratory. Figure Figure

Abstract Background: Secondary CNS involvement (SCNS) is a detrimental complication seen in ~5% of patients with diffuse large B-cell lymphoma (DLBCL) treated with modern immunochemotherapy. Data from older series report short survival following SCNS, typically <6 months. However, data in patients that develop SCNS following primary therapy that contains a rituximab-based-regimen as well as the impact of more intensified treatment for SCNS are limited. Aims: The aims of this study were to i) describe the natural history of SCNS in a large cohort of patients treated with immunochemotherapy, and ii) determine prognostic factors after SCNS. Patients and methods: We performed a retrospective study of patients diagnosed with SCNS during or after frontline immunochemotherapy (R-CHOP or equivalently effective regimens). SCNS was defined as new involvement of the CNS (parenchymal, leptomeningeal, and/or eye) in patients without known CNS involvement at the time of first pathologic diagnosis of DLBCL. Patients were identified from local databases and/or regional/national registries in Denmark, Canada (British Columbia), Australia, Israel, US (University of Iowa/Mayo Clinic SPORE), and England (Guy's and St. Thomas' Hospital, London). Clinico-pathologic and treatment characteristics at the time of SCNS were collected from medical records. Results: In total, 281 patients with SCNS diagnosed between 2001 and 2016 were included. Median age at SCNS was 64 (range 20-93) years and male:female ratio was 1.3. SCNS occurred as part of first relapse in 244 (87%) patients and 112 (40%) had documented concurrent systemic disease at the time of SCNS. The median time from initial DLBCL diagnosis to SCNS was 9 months, which was similar for patients treated with (N=76, 27%) or without upfront CNS prophylaxis (N=205, 73%) (10 vs 9 Mo; P=0.3). The median post-SCNS OS was 4 months (interquartile range 2-13) and the 2yr survival rate was 20% (95% CI 15-25) for the entire cohort. Associations between clinicopathologic features, management strategy, and post-SCNS survival are shown in Table 1, which excludes patients who did not receive any treatment against SCNS, patients treated with steroids alone, and a patient with unavailable treatment information (n=43, 15%). In multivariable analysis, performance status >1, concurrent leptomeningeal and parenchymal involvement, SCNS developing before completion of 1st line treatment, and combined systemic and CNS involvement by DLBCL were associated with inferior outcomes. Upfront CNS prophylaxis did not influence post-SCNS OS. High-dose methotrexate (HDMTX) and/or platinum based treatment regimens (i.e. ICE, DHAP, or GDP [+/- IT treatment and/or radiotherapy], N=163) for SCNS were associated with reduced risk of death (HR 0.45 [0.32-0.62, P<0.01]). The 2yr post-SCNS survival for patients treated with HDMTX and/or platinum-based regimens (N=163) was 29% (95% CI 22-37). For patients with isolated parenchymal SCNS, single modality treatment with radiotherapy resulted in 2-yr OS of 19% (95% CI 8-35). For the subgroup of 49 patients treated with HDMTX- and/or platinum-based regimens for isolated SCNS after 1st line DLBCL treatment and with performance status 0 or 1, the 2yr post-SCNS survival was 46% (95% CI 31-59). Overall, 9% of the patients received HDT with ASCT as part of salvage therapy at the time of SCNS. Amongst 36 SCNS patients without systemic involvement and in CR following intensive treatment (HDMTX and/or platinum-based treatments), 11 patients consolidated with HDT had similar outcomes to 25 patients treated without consolidating HDT (P=0.9, Fig 1) Conclusions: Outcomes for patients with SCNS remain poor in this large international cohort of patients from the immunochemotherapy era. Combined parenchymal and leptomeningeal disease, presence of systemic disease concurrent with SCNS, performance status >1, and SCNS developing during first line treatment were independently associated with inferior OS. However, a significant fraction of patients with isolated SCNS after first line DLBCL treatment and with good performance status may achieve long-term remissions after intensive regimens for SCNS. Disclosures El-Galaly: Roche: Consultancy, Other: travel funding. Cheah:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Speaker's Bureau. Kansara:Celgene: Honoraria. Connors:Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Seymour:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Villa:Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria, Research Funding.

Abstract Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is a rare and aggressive hematological malignancy. Unlike B-cell ALL, apart from age and presenting WBC, additional prognostic factors remain largely unknown. Additionally, the prognostic impact of a monosomal karyotype, which has a negative impact on survival in myeloid neoplasms, remains to be determined in T-ALL (Kenderian et al, BCJ 2013) Aim: To study predictors of survival including the role of a monosomal karyotype in T-ALL. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic Rochester were identified. All clinical and pathologic data including FISH studies and cytogenetics were retrospectively reviewed. Chi-square test was used to compare variables. Survival was estimated and compared using the Kaplan-Meier Method and log-rank test. Univariate and multivariate analysis was performed using the Cox regression model. Results: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified, 41 had acute lymphoblastic lymphoma (LBL), and 51 (55%) acute lymphoblastic leukemia (ALL). Median age at diagnosis was 33 years (range; 18-88 years) with 72%males. Median follow up of our cohort was 25 months (range; 0.9-260 months) during which time 42 deaths (45%) were documented. A. Baseline characteristics: Fifty six (67%) had constitutional symptoms, and 63 (77%) had lymphadenopathy at diagnosis. Mediastinal mass was identified in 49 (55%) pts with palpable splenomegaly in 16 (20%) pts. Fifty one (58%) pts had extranodal disease, and 17 (19%) pts had CNS involvement. Pleural and pericardial effusion were evident in 16 (19%), and 6 (7%) pts, respectively. Median laboratory values included; LDH 288 U/L (115-6590), hemoglobin (Hb) 12.8 g/dl (4.5-18.2), WBC 8.65 x109 (1.4-406), platelets 169 x109 (8-485), bone marrow blasts 29% (0-99). B. Treatments: Induction therapies were variable and included; 11 (12%) CHOP like regimens, 7 (8%) modified NHL regimens (Asparginase+CHOP), 54 (58%) ALL like regimens (CALGB 9111, E2993, or HyperCVAD), 13 (14%) Pediatric regimens (ALL 10403, CCG 1961, BFM, Augmented BFM, GRAALL 2003, or Hoelzer regimen), with 7 (8%) patients' receiving palliative care only. Seventy-one (77%) pts achieved complete remission (CR1) during induction therapy while eight pts had refractory disease (8%). Thirty-three (35%) pts underwent stem cell transplant; 7 (21%) autologous and 26 (79%) allogeneic. Forty one (44%) pts had disease relapse and median time to relapse was 10.8 months (range; 8.2-16 months) C. Predictors of survival: In univariate analysis, that included age > 60 years, leukocyte count Hb, Plt, Blast percentage, mediastinal mass, LDH and CNS involvement, only age >60 and CNS involvement were predictors of inferior survival and both retained significance in the multivariable analysis with HR 3.9 (CI 1.5 - 9; p=0.0055) and 2.8 (1.3 - 5.7; p =0.0085), respectively (Figure 1 and 2). In this cohort age >60 was a better stratification that the conventionally used age above 40 (p = 0.1). Among 56 pts with evaluable cytogenetics data, 7 (13%) pts had MK which did not have an impact on survival with HR 1.9 (CI 0.4-5.6; p=0.33). Conclusion: In this large cohort of adult T-ALL patients, we observed that age >60 years and CNS involvement were independent predictors of inferior survival. MK was infrequent, but unlike in myeloid neoplasms, does not seem to impact overall survival. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Spectrum: Research Funding; Valeant Pharma: Equity Ownership.

Abstract Background: Acute T-cell lymphoblastic leukemia (T-ALL)/ lymphoma (T-LBL) are immature T-cell malignancies with very poor outcomes. In patients with relapsed disease, survival is often < 12 months (Marks et al, Blood, 2009). Prognostic correlates and treatment outcomes after relapse remain largely unknown. Aims: To evaluate prognostic correlates and treatment outcomes in patients with relapsed T-ALL/LBL. Methods: After IRB approval, 92 consecutive patients with T-cell ALL/LBL were identified. 41 patients with relapsed disease after achieving a first complete remission (CR1) were included in the study group. Features at the time of relapse were retrospectively abstracted and analyzed. Survival time after relapse was calculated from the time of relapse until death or last follow-up. Conventional methods were used for statistical analysis. Results: A. Baseline characteristics of all patients 92 patients were identified [41 LBL, 51 ALL]. Median age was 33 years (range; 18-88) and 66 (72%) were males. Median follow-up was 25 months (range 0.9-260). 13(14%) received palliative care or were lost to follow-up before treatment initiation. At last follow-up, there were 41 (52%, n = 79) relapses and 42 (46%, n = 92) deaths. Of 79 patients, 71 (90%) achieved a CR1 and 8 (10%) had primary refractory disease. Comparisons between ALL and LBL revealed expected differences in presenting features such as frequency of primary mediastinal mass at presentation in LBL and high leukocyte count in ALL. Significant differences in treatment were seen. Asparaginase-based and ALL-directed therapy were more common in the ALL group (71% vs. 45%, p = 0.009; 88% vs. 71%, p = 0.04). 13 (81%) LBL and 14 (27%) ALL underwent allogeneic SCT. The remaining three in each group underwent autologous SCT in CR1. B. Characteristics of relapsed patients 41 relapsed after achieving CR1 [23 LBL, 18 ALL]. Median time to relapse was 8.0 months (range 2.3-130), with no difference between ALL and LBL groups. Median age was 34 years (range 19-71) and 29 (71%) were males. Median follow-up after relapse was 7.2 months (range 0.3-207). At time of last follow-up, there were 30 (73%) deaths, 25 (61%) achieved a second complete remission (CR2) and 14 (34%) had persistent disease. 12 (48%) had relapse following CR2. 34 (83%) relapsed following CR1 after induction chemotherapy alone. 6 (15%) and 1 (2%) relapsed following allogeneic and autologous SCT respectively. 27 (66%) had BM involvement, 5 (12%) had CNS involvement, 13 (32%) had mediastinal involvement, and 3 (7%) had isolated extramedullary relapse. Ten (43%) patients with LBL relapsed with ALL. Of 27 patients with available data, 9 (33%) had high-risk cytogenetics at relapse, defined as ≥ 5 chromosomal abnormalities and/or markers known to confer an unfavorable prognosis. 16 of these 27 patients had follow-up cytogenetic studies performed, of which 8 (50%) had evidence of clonal evolution. Patients were treated with up to five regimens. 12 (31%) received asparaginase-based therapy and 13 (33%) received nelarabine with CR2 rates of 75% and 25% respectively. Median number of regimens needed to achieve CR2 was one. 18 (46%) went onto SCT following CR2: 14 (allogeneic), 3 (autologous), and 1 (donor lymphocyte infusion). The majority received myeloablative conditioning (92%). C. Outcomes and prognostic correlates for survival after relapse Median survival following relapse was 8.2 months (IQR 4.1-21.3) and did not differ between LBL and ALL. Nine (36%) who achieved CR2 are alive at time of last follow-up. 25 (61%) achieved CR2, but 12 (48%) relapsed following CR2, with median time to second relapse of 7.6 months (IQR 4.7-14). Nine of 18 who underwent SCT following CR2 had disease relapse (8 allogeneic, 1 autologous). Only BM involvement at relapse significantly correlated with post-relapse survival (HR 2.4 [1.1, 5.1], p = 0.03). Clonal evolution, high-risk cytogenetics, nelarabine therapy, achieving CR2, and SCT were not independent predictors of survival in our small subset of patients. Conclusion: Patients with relapsed T-ALL/LBL have dismal outcomes, in spite of advances in therapy with newer agents such as nelarabine and the use of allogeneic SCT. Regardless of T-ALL/LBL subtype, BM involvement at relapse appears to be a significant factor negatively impacting post-relapse survival. Further studies are needed to validate these findings. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Background. Diffuse large B-cell lymphoma (DLBCL) is curable for the majority of patients treated with anthracycline based immunochemotherapy (IC). While most patients achieve response to initial therapy, a subset of patients are refractory to initial IC or become refractory to subsequent salvage therapies. Prognosis in this setting is very poor. Here we determine the incidence of refractory disease from a large cohort of DLBCL prospectively followed from diagnosis in the IC era and assess outcomes in these patients. Methods. Patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) within 9 months of diagnosis. Patients were followed for relapse, retreatment, and death; all events were validated by medical record. This analysis includes patients with DLBCL or primary mediastinal B-cell lymphoma (PMBCL) who received initial treatment of anthracycline based immunochemotherapy; patients with primary CNS lymphoma or post-transplant lymphoproliferative disorders were excluded. Response to therapy was retrospectively classified per 2007 Revised Response Criteria for Malignant Lymphoma from available clinical and radiology records. Refractory disease was defined as having a best response to any systemic therapy of stable disease (SD), progressive disease (PD), or relapse within 12 months of autologous stem cell transplantation (SCT). We also examined patients with transient response to IC as defined by achieving an interim response (CR or PR) but having progressive disease at or prior to the end of the planned number of cycles of IC. Results. 1039 patients with DLBCL or PMBCL lymphoma were enrolled in the MER from 2002-2012 and treated with R-CHOP or comparable IC. Median age at diagnosis was 62 years (range 18-91) and 577 (56%) were male. At a median FU of 60 months (range 1-148), 136 patients developed refractory disease. The median age at diagnosis of patients with refractory disease was 62 years (range 19-87). The cumulative incidence of refractory DLBCL was 11.3% at 2 years (95%: CI: 9.5-13.4) and 13.1% at 5 years (95% CI: 11.2-15.4). The median overall survival after becoming refractory was 4.7 months (95% CI: 4.1-5.5) with a 1 year survival rate of 21% (95% CI: 15%-30%). The median number of therapies before becoming refractory was 2 with 35 patients becoming refractory following their first therapy (i.e. IC), 83 patients becoming refractory after their 2nd therapy, and 23 patients becoming refractory after their 3rd or later therapy; 27 patients had received stem cell transplant prior to becoming refractory. Outcomes were poor regardless of when patients became refractory (figure). Patients received a median (range) of 2 (0-8) treatments after becoming refractory with 40% (N=54) attempting subsequent platinum based salvage therapy and 14% (N=9) proceeding to ASCT, of which only 6 remain alive in long-term remission. 41 patients (30%) were treated on clinical trials after becoming refractory. Response rate for the first therapy after becoming refractory was 21%, while 29% of patients had a response to any subsequent therapy. Once patients became refractory, there was no difference in survival based on response at end of initial IC (p=0.33), cell of origin at diagnosis (p=0.64), IPI at diagnosis (p=0.33), or age when refractory (p=0.66). Outcomes in patients with transient response to IC (n=58) were poor, with the majority (N=37, 63%) becoming refractory to subsequent therapy. Median OS after first relapse was 6.7 months in patients with transient response to IC, which was equivalent to patients refractory to IC (p=0.99). The majority of patients with transient response to IC (69%) were next treated with platinum based salvage therapy which had a response rate of 40%. Ultimately 15 of the 58 patients (26%) proceeded to transplant, of which only 5 (9%) achieved long-term remission. Conclusions. Approximately 13% of patients with DLBCL become refractory to treatment in their disease course. Outcomes once patients become refractory are extremely poor regardless of when patients become refractory. Standard prognostic factors are no longer predictive of outcome and stem cell transplant had limited benefit in this group of patients. Patients with transient response to initial immunochemotherapy should be included when classifying patients as refractory. New therapy strategies are needed in the refractory setting. Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Farooq:Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding.

Abstract Introduction Outcomes have improved in treating lymphoid malignancies but relapse remains an ongoing issue. The mTOR inhibitor, everolimus (RAD) and lenalidomide (LEN) have both shown clinically significant activity as single agents in patients with relapsed and refractory (R/R) Hodgkin (HL) and non-Hodgkin (NHL) lymphomas. The low toxicity and differing mechanisms of action were explored further by combining these active agents. A phase I/II clinical trial of the mTOR inhibitor everolimus (RAD) and lenalidomide (LEN) was designed to explore the tolerability, toxicity and to determine the MTD of this combination for Phase II study. The phase I data is reported here. Methods This Phase I/II trial for patients with R/R lymphoid malignancy opened at Mayo Clinic between January 2011 and May 2013 and utilized a standard cohort of 3+3 design to determine the MTD of the combination. Eligibility required age≥18, biopsy proven relapsed or refractory NHL or HL, ECOG PS 0, 1 or 2, measurable disease, Hb >9g/dl, ANC ≥1200/uL, platelet ≥ 50,000/uL, creatinine ≤1.5xULN and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Dose limiting toxicity was defined in cycle 1 as Gr 4 neutropenia ≥7days or platelets ≤ 25,000 ≥7days, grade 4 infection or grade ≥3 non-Heme toxicity at least possibly related to treatment per CTCAE v4.0. The starting dose (level 0) was RAD 5mg daily + LEN 10 mg/d X 21d in a 28-day cycle. Results Twenty-five patients were enrolled on the phase I portion and 23 are evaluable for analysis. The median age was 63 years (23-82) and 18 (78%) were male. Sixty-five percent had stage IV disease and 43% had 4 or more prior treatments (1- ≥5) including stem cell transplantation in 39%. Histologies included HL (n=3) and NHL (n=20)(DLBCL = 11, FL-III = 2, LPL = 3, MCL = 1, MF = 1, and other = 2). Two DLTs (rash, Gr4 neutropenia) were reported at the starting dose (level 0) and the protocol was amended for DLT definition change. At dose level -1 (RAD 5mg daily + LEN 5mg/d X 21d) a DLT (Gr4 neutropenia) was seen in only 1 of 6 patients so the study was re-opened to dose level 0 and 3 additional patients were treated without developing a DLT. At dose level +1 (RAD 5 mg daily + LEN 15mg/d X 21d) 1 Gr3 rash occurred and 2 patients experienced Gr4 neutropenia. Therefore the MTD was determined to be RAD 5mgdaily + LEN 10 mg/d X 21d. At least 1 Gr≥3 adverse event was seen in 91% of patients. The most common Gr≥3 toxicities were neutropenia (57%), leucopenia (52%), thrombocytopenia (39%), fatigue (22%), and anemia (13%). Eight of 23 patients (35%) had Gr≥3 infection. Five patients discontinued study due to adverse events. One death on study occurred due to disease progression. Three patients continue on therapy. Responses have been seen in 4 patients and 10 patients have stable disease, encouraging signs in this heavily pretreated population. Conclusions This phase I/II trial of everolimus and lenalidomide in malignant lymphoma shows the combination to be tolerable with neutropenia as the main dose limiting toxicity. The MTD of this combination is RAD 5mg daily and LEN 10 mg/d X 21 d. Encouraging responses were seen. The phase II study has opened with 2 patients accrued to date. Updated results will be presented. This trial is sponsored by Novartis and Celgene Disclosures: Reeder: Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding. Off Label Use: lenalidomide and everolimus are not approved for treatment of lymphoma. Nowakowski:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Witzig:Celgene: Research Funding.