Abstract: Despite continuing improvements in the management of classical Hodgkin lymphoma (cHL), relapse remains associated with a risk of lymphoma‐related mortality. The biological composition of relapse tumour biopsies shows interpatient variability, which can be leveraged to design prognostic biomarkers. Here, we validated the RHL30 assay, a previously reported gene expression model in an independent cohort of 41 patients with relapsed cHL. Patients classified as high‐risk by the RHL30 assay had inferior failure‐free survival (FFS) after autologous stem cell transplantation (2‐year FFS 41% vs. 92%, P  = 0·035). The RHL30 model is a robust biomarker that risk‐stratifies patients considered for autologous stem cell transplantation.

Abstract: Background Stage I/II or early-stage follicular lymphoma (ESFL) is considered potentially curable with radiotherapy (XRT). While XRT does achieve local disease control in 〉 90% of cases, more than half the patients (pts) relapse by 10 years (yr), generally outside of the radiation field. A recent randomized controlled trial (TROG 99.03) demonstrated that combined modality therapy (CMT), with sequential XRT and systemic therapy, significantly improved PFS but not overall survival (OS) compared to XRT alone in ESFL. However, only half the pts were staged with 18F‐FDG positron emission tomography and computed tomography (PET) and 58% of CMT pts did not receive rituximab.Compared with CT staging, 20-60% of cases are upstaged by PET. Consequentially, there are limitations in applying this trial to modern populations. Despite the support of current guidelines, only one third of pts in clinical practice are treated with XRT. This suggests a need to better understand the role of other treatments, including watchful waiting (WW), in the PETera. Our aim was to compare outcomes with real-world treatment approaches in rigorously staged ESFL patients. Methods We conducted an international, multicenterretrospective study of stage I and II FL pts rigorously staged with bone marrow biopsy and PET. Eligible pts were 〉 18yr with newly-diagnosed grade 1-3A FL and ≥3 months follow up. Primary outcome measures were overall response rate (ORR), progression free survival (PFS), OS and risk of transformation. Survival curves were estimated with the Kaplan-Meier method and uni- and multi-variate analysis was performed using Cox regression model. Results A total of 387 pts treated at 13 Australian and 3 Canadian centres between 2005-2017 were studied. Median follow-up was 45 months (range 3.1 - 164.0).5-yrPFS and OS rates were 73.5% (95% CI 66.0-78.5) and 94.4% (95% CI 89.4-93.6) respectively. 22 patients had stage IE duodenal FL with 5-yr PFS and OS rates of 100% and 100% respectively. Considering the unique biology and favorable prognosis of duodenal FL, these cases were excluded from subsequent analyses. Treatment approaches 365 pts included WW (defined as absence of treatment within 6 months from diagnosis) (23.2%), XRT (46.8%), immunochemotherapy (17.2%) and CMT (12.6%). Treatment regimens were: R-CHOP (48.1%), R-CVP (24.4%), BR (9.9%), other (17.6%). First-line therapies for actively treated pts yielded comparable ORRs of 95.6%, 96.7% and 95.9% for XRT, immunochemotherapy and CMT, respectively (P=0.94). Overall, 18.2% of pts relapsed at distant sites, 88.2% of all relapses. Treatment cohorts differed in baseline clinical characteristics. WW pts were significantly older (P=0.007) but otherwise comparable to those treated actively. Compared to chemotherapy or CMT pts, those treated with XRT had more favorable features including fewer B symptoms (4.2% vs 11.2% p=0.029), bulk (≥7cm) (6.8% vs 25.3%, p 〈 0.001), nodal sites (≥3) (1.9% vs 9.5% p=0.005) and a higher frequency of stage I FL (73.1% vs 42.1% p 〈 0.001). Outcomes differed among treatment approaches. Active treatment was associated with superior PFS compared with WW pts (HR 0.54 p=0.004) however, 49.4% of WW pts remained untreated at 5-yrs (Fig 1a). Considering actively treated pts, systemic therapy (immunochemotherapy or CMT) was associated with superior PFS compared to XRT by univariate analysis (HR 0.49, p=0.009) (Fig 1b). This association remained after multivariate adjustment for bulk, B symptoms, nodal sites and stage (HR 0.41 p=0.002). Treatment with immunochemotherapy and CMT demonstrated a comparable PFS (p=0.2). Maintenance rituximab (n=45) was associated with superior PFS compared with observation after systemic therapy (HR 0.24, p=0.017). There were no differences in OS among treatment approaches (P=0.734). There was a higher incidence of transformation in XRT pts compared to systemic therapy pts (6.4% vs 1.6% p=0.046). Conclusion In the largest assessment of rigorously-staged ESFL pts in the PETera, pts treated with systemic therapy (chemotherapy or CMT) had a superior PFS and a lower rate of transformation compared to pts treated with XRT, although treatments were not randomized. These findings are similar to the TROG 99.03 trial and challenge the paradigm that ESFL should be uniformly treated with XRT alone. Half the pts observed from diagnosis remained treatment-free at 5-yrs, suggesting that WW may be appropriate in selected pts. Disclosures Tobin: Celgene: Research Funding; Amgen: Other: Educational Travel. Tam:Roche: Honoraria; Roche: Honoraria; Pharmacyclics: Honoraria, Travel funding; Pharmacyclics: Honoraria; Beigene: Honoraria, Other: Travel funding; Beigene: Honoraria, Other: Travel funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Gilead: Honoraria; AbbVie: Honoraria, Research Funding. Abro:Amgen: Other: education support congress attendance; Celgene: Other: education support congress attendance; Bristol-Myers Squibb: Speakers Bureau; Janssen: Other: education support congress attendance; Novartis: Consultancy. Hawkes:Bristol Myers Squibb: Other: Speaker fee, Research Funding; Takeda: Other: Speaker fee; Astra Zeneca: Research Funding; Merck Sharpe Dohme: Research Funding; Merck KGA: Research Funding; Celgene: Other: Advisory board, Research Funding; Merck: Other: Advisory board; Roche: Other: Speaker fee; advisory board. Talaulikar:Amgen: Consultancy, Honoraria; Roche: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Research Funding; Novartis: Honoraria, Speakers Bureau. Gandhi:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Introduction: Classical Hodgkin lymphoma (cHL) typically affects younger patients but 15-35% are & gt;60 years. The age used to define an elderly population has varied but age 60 is frequently used. A clinically relevant definition of older age could be based on the use of alternate treatments due to different efficacy and/or toxicity. Treatment outcomes may also be influenced by tumor biology and patient comorbidity that vary with age. We evaluated the effect of age on treatment outcomes in cHL. Methods: All cHL patients treated at our centre between Jan 1999 and Dec 2015 were retrospectively analyzed. Clinical data were obtained from prospectively collected Lymphoma database and additional data was manually retrieved. Treatment for localized disease was combined modality (2-4 cycles of ABVD and potentially 6 cycles for bulk disease & gt; 10 cm; radiation doses 20-35 Gy) with advanced disease typically receiving chemotherapy alone (ABVD 6-8 cycles). Older patients received individualized treatment. We used the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), (Sorror Blood 2005) as the elements can be abstracted retrospectively. Results: 607 patients were identified; 14% were & gt;60 years and 6% were age & gt;70. Baseline characteristics are outlined in table 1. Patients & gt;70 presented more frequently with high-risk HCT-CI and worse ECOG PS. Patients & gt; 60 presented more frequently with advanced stage (61-70 age group: 40%; & gt;70 years: 46%). 65% of the patients age & gt;70 presented with an IPS of & gt;3. Chemotherapy alone approaches were used more commonly in older patients (age 61-70: 40%; age 70+: 51%) than in those & lt;60 years (25%). Within the whole cohort 12 patients received non-anthracycline based treatment ( & lt;60: n=4; 61-70: n=1; and & gt;70: n=7).For patients & lt;60 and & gt;70 this decision was made due to prior comorbidities that precluded the use of standard treatment, and for the patient in the 61-70 was because of acute toxicity with ABVD-based chemotherapy. Treatment was discontinued in 33% of the patients & gt; 70 (77% due to toxicity), 21% in the 61-70 years group (30% toxicity) and 6% in patients & lt;60 (29% toxicity). Patients & gt; 70 had higher rates of grade 3-5 febrile neutropenia (28% versus 15% [age 61-70] and 7% [age & lt;60]). Bleomycin toxicity was more common in older patients (age & gt;70: grade 3-4 events 12% of the patients with discontinuation in 66%; age 61-70: 13% with discontinuation rate of 20%) compared to a 1% rate of grade 3-5 events in age & lt;60. There was a grade 5 episode of febrile neutropenia in & gt;70 group and 1 death related to bleomycin in age & lt;60. With a median follow up of 8.6 years, the 10-year OS and PFS were 80.5% and 71.2%, respectively. By age-group, the 10-year OS was 88% ( & lt;60 years), 57% (61-70 years) and 15% (age & gt;70 years); (p & lt;0.001) (Figure 1a-b). In multivariable analysis for OS, age 61-70 (HR 2.44, p=0.002) and age & gt;70 (HR 5.72, p=0.001), non-anthracycline based chemotherapy (HR 3.69, p & lt;0.001), high-risk HCT-CI (HR 3.03, p=0.001) and ECOG 2-4 (HR 1.8, p=0.017), were significant. Age & gt;70, type of chemotherapy, high-risk HCT-CI, and advanced stage were significant for PFS in the multivariable analysis (Table 2a-b). Death due to disease or toxicity at 10 years was 13.6% (age & lt;60: 9.7%, 61-70 years: 23.2%; and for age & gt; 70: 50.7%; [p= & lt;0.001]) (Figure 2a-b). Multivariable analysis for cause-specific survival identified age & gt;70 years (HR 4.04, p= & lt;0.001), extranodal disease (HR 2.57, p=0.001) and ECOG 2-4 (HR 2.10, p=0.010) as significant predictors(Table 3). Conclusions: Age & gt;70 years is a clinically relevant age cutoff as it has additional prognostic significance and greater rates of treatment discontinuation and toxicity compared to age 60. The HCT-CI is a useful predictor of outcome in cHL and should be validated prospectively. In multivariable analysis, age, type of treatment, comorbidity and ECOG performance status are independent predictors of OS. Further studies are ongoing to validate these findings and assess biologic differences in older versus younger cHL patients. Disclosures Tsang: Nordic Nanovector: Research Funding. Kridel:Gilead Sciences: Research Funding. Kukreti:Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Prica:Celgene: Honoraria; Janssen: Honoraria. Kuruvilla:Janssen: Research Funding; Roche: Honoraria; Novartis: Honoraria; Merck: Honoraria; Gilead: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Celgene: Honoraria; BMS: Honoraria; BMS: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Astra Zeneca: Honoraria; Janssen: Honoraria; Roche: Research Funding; Amgen: Honoraria; Seattle Genetics: Honoraria; Karyopharm: Honoraria.

Abstract: Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic inflammatory clinical syndrome that can be primary/familial or secondary to a variety of underlying conditions. The 2004 diagnostic criteria for HLH require 5 out of 8 of the following clinical and pathological variables to be present: fever, splenomegaly, cytopenia in at least 2 lineages, hypertriglyceridemia/hypofibrinogenemia, haemophagocytosis on pathology examination, low/absent NK cell activity, ferritin greater than 500µg/L or soluble IL-2 receptor (sCD25) greater than 2400 U/mL. At least 5 of these criteria must be met, as each one lacks specificity. With regard to the pathology detection of haemophagocytosis, the sensitivity and specificity reported in the literature were 83% and 60% respectively. Indeed, a degree of haemophagocytosis can be seen outside the context of HLH. Furthermore, some of the diagnostic features of HLH may not be useful when applied to single cases because they may be intrinsic to the underlying condition. Therefore, we wondered whether the histopathological diagnosis might be improved. We investigated whether testing for S100B expression in macrophages might render the detection of haemophagocytosis more specific and sensitive. S100B is a marker of macrophage activation, and can routinely be detected by immunohistochemistry. S100B has pro-inflammatory properties and has been shown to affect macrophage function. It is typically expressed in macrophages of Rosai-Dorfman disease apart of having also a tissue-specific expression pattern, marking melanocytes as well as Langerhans cells and other subsets of dendritic cells. A natural language search of the pathology database at our institution identified 32 patients with bone marrow samples reporting haemophagocytosis as evaluated on bone marrow smear preparations, between January 2002 and July 2015. Cases that did not have available paraffin-embedded bone marrow trephine biopsy and clinical data were excluded. The bone marrow samples of three patients without haemophagocytosis and without any clinical features of HLH were used as controls: a new diagnosis of acute leukemia, a follow-up of acute leukemia post-transplant and a known lymphoma patient with unexplained pancytopenia. Clinical parameters relevant to the diagnosis of HLH were evaluated. Cases were clinically categorized as diagnostic for HLH (≥5 criteria), clinically likely ( 〈 5 criteria, but clinical presentation consistent) or clinically non suspicious ( 〈 5 criteria and clinical presentation not consistent with HLH). Stains for S100B and CD68 were performed. The percentage of S100B positive cells of all bone marrow cells as well as the percentage of CD68 positive macrophages was calculated from 500-cell counts using a 40x objective lens. The median patient age was 57 years (range 18-80). Underlying clinical diagnoses are reported in Table 1. Expression of S100B ranged from 0-76.4%. Cases without morphological evidence of haemophagocytosis had less than 1% S100B-positive cells. Cases with presence of haemophagocytic cells showed various levels of S100B-positive cells. Of interest, 〉 10% S100B-positive cells (of all cells) was 100% specific for cases meeting ≥4 HLH criteria, 91% specific for cases clinically likely HLH or confirmed HLH. The sensitivity was 60% for cases meeting ≥4 HLH criteria, 52% for cases being likely HLH or confirmed HLH. Percentage of CD68-positive cells or S100B/CD68 ratio did not add relevant information. The high specificity of S100B expression by immunohistochemistry indicates it may be an additional diagnostic feature of HLH. Of note, the test is available in routine immunohistochemistry laboratories. Since not all cases of HLH show increased numbers of S100B-expressing macrophages, the test does not obviate the need for the 2004 criteria. Serological immunoassays for S100B have been developed for use in the context of brain disease/injuries and malignant melanoma. Based on our data, we intend to further investigate the sensitivity and specificity of S100B as a serological marker of HLH. Disclosures Kuruvilla: BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy, Honoraria; Leukemia and Lymphoma Society Canada: Research Funding; Merck: Consultancy, Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Lundbeck: Honoraria.

Abstract: Practices in early-stage FL are variable and include radiation alone, systemic therapy, CMT, or observation. Each practice resulted in similar excellent outcomes; randomized trials are required to determine the optimal treatment.