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Introduction Histiocytic neoplasms are rare disorders of the monocyte-macrophage-dendritic cell lineage that pose significant management challenges to the clinicians. Over the last five years, there has been emerging data on the role of MAPK/ERK pathway (RAS-RAF-MEK-ERK) in their pathogenesis. In this study, we report the molecular alterations among patients with histiocytic neoplasms seen at our institution. Methods We pursued target-capture next generation sequencing (NGS) on tissue specimen of patients with various histiocytic neoplasms- Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), Rosai-Dorfman disease (RDD), histiocytic sarcoma (HS), and Langerhans cell sarcoma (LCS). We used three NGS platforms, Tempus® xO (1,714 genes), Tempus® xT (596 genes), or Foundation One® CDX (324 genes). All platforms used formalin-fixed paraffin-embedded tumor tissue specimens for detection of substitutions, insertion and deletion alterations, and copy number alterations, and gene rearrangements. The Tempus assays also utilized matched blood or saliva samples for germline DNA sequencing in addition to whole-transcriptome RNA sequencing. The tumor cellularity threshold for pursuing RNA sequencing was 30% so the test was not pursued specimens for lower cellularity. Results We included 31 cases with histiocytic neoplasms in this study. The disease distribution was as follows: ECD (n=6), LCH (n=7), RDD (n=12), ECD-RDD overlap (n=3), HS (n=2), and LCS (n=1). Among the 13 patients with ECD and LCH, BRAF-V600E mutations were found in 8 (62%) cases. We found several novel DNA alterations in this study in all disease groups: ECD (BRAFV471F), LCH (MAP2K1 in-frame deletion), and RDD (frameshift mutations of DNMT3A, SMARCA4, KMT2A, and CDC73 truncation). In one LCH patient without any DNA alterations, we found MAPK1 and MAP2K1 overexpression on RNA sequencing. We also had two cases with HS, both of which were found to have KRAS exon 3 mutations. One of these cases had concomitant JAK2V617F+ myelofibrosis and the tissue specimen for HS demonstrated TET2 and SRSF2 mutations as well. Our cohort included one patient with multifocal lymph node LCS that demonstrated NRAS and TP53 mutations, who did not respond to MEK-inhibitor therapy. Alterations in epigenetic regulators (TET2, DMNT3A, KMT2A, ASXL1) were found in 5 (16%), potentially suggesting clonal hematopoiesis in a subgroup of histiocytosis. Conclusions Histiocytic neoplasms demonstrate diverse somatic oncogenic alterations. In our study, we noted several novel alterations beyond the MAPK-ERK pathway in RDD that may point toward other potentially pathogenic mechanisms for these rare disorders. In cases where the DNA sequencing does not reveal pathogenic alterations, transcriptome analysis may aid in the diagnosis and management. OffLabel Disclosure: Trametinib use for Langerhans cell sarcoma

Purpose: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder that presents with a wide spectrum of clinical diseases, ranging from single-organ lesions to systemic disease. Although previously thought of as an immune disorder, LCH was reclassified as an inflammatory myeloid neoplasm in the 2016 Histocyte Society classification after discovery of BRAF V600E or MAP2K1 gain-of-function mutations and evidence of clonality in most LCH patients. In this revised classification, LCH was divided into single-system LCH, pulmonary LCH, or multisystem LCH. However, there is a lack of data on clinical features and outcomes in the subgroup of "unifocal" non-pulmonary LCH in adults. In this study, we sought to address the gaps in knowledge for unifocal adult LCH utilizing our institution's experience over 20 years. Methods: We retrospectively reviewed the medical records of 189 adult patients (defined as >18 years old at diagnosis) with histopathologically confirmed LCH who were seen at our tertiary referral center between 1997 and 2018. Of these, 44 met criteria for unifocal LCH at diagnosis after careful exclusion of other sites of disease involvement. Results: We included 44 adult patients with unifocal LCH at diagnosis, with median age 42 years (range 19 to 88) and 55% males. 84% were Caucasians and 50% were smokers. Most commonly involved disease sites included bone (43%), skin (25%), pituitary (14%), and gastrointestinal (11%), with common presenting symptoms of head pain/swelling (25%), skin rash (20%), abdominal pain/diarrhea (11%), and diabetes insipidus (9%). Resection/excision was the most common first line therapy in 24 patients (63%); none had local recurrence and 3 patients developed recurrence at a new site. Radiation was the second most common therapy in 6 patients, with an overall response rate of 83%; none had local recurrence and 1 patient had recurrence at a new site. Other less common first-line treatments included resection followed by radiation (2), topical immunosuppression (2), dexamethasone (1), cladribine (1), smoking cessation (1), and observation (1) (Table 1). Cladribine used as first-line therapy for pituitary LCH resulted in progressive disease, but cladribine used as second-line therapy in 2 cases (including one who had progressed to multisystem disease) resulted in partial remission with no further recurrence in both cases. Patients were followed for a median of 3.8 years (range 0.1 to 18.8), with 5 patients lost to follow-up. By time of last follow-up, 11 (28%) had developed recurrence: 1 had local recurrence, 5 developed disease at a new site within the same system (skin or bone), and 5 developed multisystem disease (Figure 1). Median time to recurrence was 2 years (range 0.2 to 6.6). 2 out of 5 patients tested for BRAF had a V600E mutation, both of whom had isolated unifocal bone disease and remained in complete remission following resection at time of last follow-up. Median overall survival (OS) from time of diagnosis was not reached and overall 5-year OS was 94%. 3 patients died, only 1 of progressive LCH. Conclusion: In our study, most patients with unifocal adult LCH achieved a complete remission with surgical resection or local radiation. None of the patients treated with resection or radiation developed local recurrence, but around 1 in 5 developed distant recurrence within 5 years. However, the overall prognosis was very good, and none of the patients in the cohort progressed to "high-risk" organ (liver, spleen, or bone marrow) involvement or pulmonary involvement. Further studies are warranted to assess the role of MAPK-ERK mutations in the prognosis of unifocal LCH. Disclosures Bennani: Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding. Vassallo:Sun Pharmaceuticals: Research Funding; Sun Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding.

Abstract Introduction Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved by the US FDA 10/18/2017, for the treatment of adults with relapsed or refractory (r/r) large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed lymphoma (tFL), and high-grade B-cell lymphoma (HGBCL) who have failed at least two prior systemic lines of therapy. In the pivotal ZUMA-1 trial, 108 patients (pts) with r/r DLBCL were treated with axi-cel: the best overall response rate (ORR) was 82% and complete response (CR) rate was 58%. At a median follow-up of 15.4 months, 42% of the pts had ongoing remission (Neelapu and Locke et al. NEJM 2017). Grade 3 or higher cytokine release syndrome (CRS) by Lee criteria and neurologic events (NEs) occurred in 13% and 31% of the pts, respectively. Here, we evaluated the real world outcomes of pts treated with standard of care axi-cel under the commercial FDA label. Methods and Results Seventeen US academic centers contributed data to this effort independently of the manufacturer. As of 6/30/2018, 211 pts were leukapheresed with intention to manufacture commercial axi-cel. Of these, 165 (78%) pts completed axi-cel infusion as of 6/30/18 and a further 23 (11%) pts are scheduled for axi-cel infusion in July 2018. Of the 23 remaining pts, 7 (3%) received axi-cel therapy on ZUMA-9 expanded access trial (NCT03153462) due to non-conforming cell therapy product, 15 (7%) pts died before axi-cel infusion (14 from lymphoma progression and 1 from sepsis) and 1 (1%) patient attained CR from bridging therapy and was not infused. Safety was evaluable in 163 pts receiving axi-cel. Grade ³3 CRS and NEs occurred in 7% and 31% of pts. Tocilizumab was administered in 62% of pts and 57% received corticosteroids. Outside of lymphoma progression, 3 deaths occurred post-axi-cel; 1 due to HLH, 1 due to systemic candidiasis, and a third due to septic shock. There were no grade 5 NEs observed. Response assessment was done for pts infused with axi-cel and who were re-staged at day 30 and/or day 100, or were deemed to have clinical progression. Of 112 pts evaluable at day 30, ORR was 79% with 50% CR, 29% PR, 6% SD and 14% with PD. Of 39 pts evaluable at day 100, 59% of pts had ongoing response (CR 49%, PR 10%). At the time of abstract submission, more detailed patient characteristics and treatment course data were available in 134/165 pts infused. Median age was 59 (range 21-82) with 57% male. Performance status (PS) was ECOG 0-1 (81%), ECOG 2 (16%) and ECOG 3 (3%). By histology, 61% of pts had DLBCL including HGBCL, 31% had tFL and 8% PMBCL. Thirty-one percent had a prior autologous stem cell transplant. Bridging therapy between apheresis and infusion was given in 56% of patients, the majority of which consisted of chemotherapy. Sixty-six of 134 (49%) would not have met eligibility criteria for ZUMA-1 at the time of leukapheresis. Common criteria that would have made these patients ineligible for ZUMA-1 included ECOG PS >1 (n = 22), platelets <75k (n = 17), GFR <60 (n =12), active DVT/PE (n = 13), liver enzyme abnormalities (n = 10), a history of CNS lymphoma (n = 8), recent checkpoint inhibitor therapy (n = 7), ejection fraction <50% (n = 4), prior CD19 CAR T therapy (n = 4), and prior allogeneic transplant (n=2). Median time from leukapheresis to start of conditioning chemotherapy was 21 days and median time from leukapheresis to axi-cel infusion was 26 days. Median hospitalization period was 14 days. Conclusions This multicenter retrospective study delineates the real world outcomes of axi-cel CAR T-cell therapy for r/r aggressive B-cell lymphoma when used as a standard of care. Though limited by relatively short follow up, 30 day responses in the real world setting are comparable to the best responses observed on the pivotal ZUMA-1 clinical trial (Table 1). Importantly, safety appears comparable to the ZUMA-1 trial despite nearly half the pts failing to meet ZUMA-1 eligibility criteria. Updated results including PFS and OS will be presented at the meeting. L.J.N. and M.D.J. contributed equally; D.B.M., S.S.N. and F.L.L. contributed equally. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Janssen: Research Funding; Gilead: Honoraria; Juno: Honoraria; Novartis: Honoraria; Spectrum: Honoraria. Lunning:Celgene: Consultancy; Spectrum: Consultancy; Portola: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Juno: Consultancy; AbbVie: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Reagan:Seattle Genetics: Research Funding. McGuirk:Gamida Cell: Research Funding; Astellas Pharma: Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Pluristem Ltd: Research Funding. Deol:Novartis: Consultancy; Kite Pharmaceuticals: Consultancy. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Andreadis:Gilead: Consultancy; Genentech: Consultancy, Employment; Astellas: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Juno: Research Funding; Kite: Consultancy; Novartis: Consultancy, Research Funding. Munoz:Pfizer: Consultancy; Bayer: Consultancy, Speakers Bureau; Juno: Consultancy, Honoraria; Janssen: Consultancy; Genentech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Gilead: Speakers Bureau. Westin:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Vose:Kite Pharma: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria; Seattle Genetics, Inc.: Research Funding; Legend Pharmaceuticals: Honoraria; Merck Sharp & Dohme Corp.: Research Funding; Abbvie: Honoraria; Epizyme: Honoraria; Bristol Myers Squibb: Research Funding; Incyte Corp.: Research Funding. Miklos:Genentech: Research Funding; Kite - Gilead: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding. Locke:Kite Pharma: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor.

Abstract Background: Limited data exist regarding histological transformation in patients with Waldenström macroglobulinemia (WM). In this study, we present the disease characteristics, outcomes and risk factors for histological transformation in WM. Methods: Patients with WM seen at Mayo Clinic, Rochester, MN between January 1996 and December 2017 were included. Patients with aggressive non-Hodgkin lymphoma in the setting of WM were considered to have transformation. Univariate analysis for comparing baseline characteristics of transformed versus non-transformed WM was performed using Wilcoxon, Fisher's exact and Chi square tests, as appropriate. Multivariate analysis was performed using logistic regression analysis. Cox proportional hazard method was used to assess the impact on time-to-transformation. All time-to-event analyses were calculated by the Kaplan-Meier method. Results: Of 1014 patients with WM, 42 patients (4.1%) developed histological transformation. The median follow-up for the entire cohort was 9.5 years (95% CI: 8.8-10.5 years). The cumulative probability of transformation was 2.3% at 5 years, 5.3% at 10 years and 8.5% at 15 years from diagnosis of WM, respectively. There was no difference in the 5-year cumulative probability of transformation in patients with WM diagnosed between 1996-2000 (2.1%), 2001-2005 (2.9%), 2006-2010 (2.7%) and 2011-2015 (3.8%), p=0.61.The disease characteristics, laboratory parameters and histology at transformation are outlined in Table 1. In patients with DLBCL histology (n=39), Revised-International Prognostic Index was calculable in 28 patients, with 50% (n=14), 46% (n=13) and 4% (n=1) of DLBCL belonging to poor, good and very good risk groups, respectively. For DLBCL histology, 18 patients were classifiable using Hans algorithm into germinal center B-cell (GCB) type (n=3, 17%) and non-GCB type histology (n=15, 83%). The median lines of therapy received prior to transformation for the entire cohort was 2 (range 0-9), with 5 (11%) patients not having received any therapy for WM before transformation. Number of lines of alkylator-based therapy used prior to transformation [median 1 line (range 0-4)] was comparable to that used in patients in whom WM did not occur [median 1, (range 0-6); p=0.78]. The median time-to-transformation from diagnosis of WM was 4.8 years (95% CI: 2.6- 6.8 years). Overall survival (OS) from transformed disease was 3.2 years (95% CI 1.1-3.9 years). The 10-year OS of patients with WM who transformed was lower (46%) compared to patients without transformation (60%) with a trend towards statistical significance (p=0.08), Figure 1. The MYD88L265P mutation status was available in 333 patients in the entire cohort (22/42 pts in the transformed cohort and 311/972 in the non-transformed cohort. Of the 22 patients in the transformed WM cohort, 13 (59%) exhibited MYD88WT genotype and 9 (41%) exhibited MYD88L265P genotype. The risk of transformation was higher in patients with MYD88WT status [Odds ratio 6.3 (95% CI: 2.6-15.5); p<0.0001]. Additionally, serum lactate dehydrogenase (LDH) was higher at diagnosis of WM in patients who transformed, Table 2. On multivariate analysis, MYD88WT status remained an independent predictor of disease transformation [p=0.003; odds ratio 10 (95% CI: 2.1-48)]. On univariate Cox proportional hazard analysis for identifying predictors of time-to-transformation, only MYD88WT mutational status was associated with shorter time-to-transformation with a 5-year transformation rate of 15.5 % for MYD88WT versus 2.6 % with MYDL265P mutated patients [risk ratio 6.2 (95% CI: 2.5-16.4); p<0.0001]. Treatment-related details in the transformed cases were available for 37 (90%) patients; R-CHOP was the most common (41%) frontline therapy for transformation; 33% patients underwent autologous stem cell transplantation for transformed disease during their disease course. Conclusion: Histological transformation is an uncommon event in WM but confers poorer survival. MYD88WT genotype is independently associated with histological transformation a shorter time-to- transformation in patients with WM. Disclosures Ansell: Trillium: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Takeda: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Gertz:Apellis: Consultancy; Alnylam: Honoraria; spectrum: Consultancy, Honoraria; janssen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; celgene: Consultancy; Teva: Consultancy; Medscape: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

Abstract Introduction. Vitreoretinal lymphoma (VRL) is a rare ocular malignancy. Diagnosis and optimal treatment remain a challenge for clinicians. We present clinical characteristics and outcome of a cohort of 69 patients affected by vitreoretinal diffuse large B-cell (DLBCL) lymphoma treated at Mayo Clinic over a 28-year period. Methods. We accessed the Mayo Clinic Lymphoma Data Base to identify all patients > 18 years old with VRL diagnosed between 01/01/1990 and 01/31/2018. Only patients with DLBCL, confirmed at pathological review, were included. Clinical characteristics, therapies, response, relapse patterns and follow up status were collected and analyzed in the cohort and in the different subgroups: primary (PVRL, localized only in eye at diagnosis) vs concurrent (CVRL) vs secondary VRL (SVRL). Chi-squared test, Fisher's exact test and Wilcoxon's signed-rank test were used for analysis. Failure-free survival (FFS), overall survival (OS), central nervous system (CNS) and eye relapse-free survival were analyzed according to Kaplan Meier method. Differences between subgroups were compared with log-rank test. Since the group of SVRL can be affected by a survivorship selection bias, it was investigated separately for the outcome analysis. Results. A total of 69 patients with vitreoretinal DLBCL were included. At diagnosis, 33 (48%) were PVRL, 18 (26%) CVRL (eye plus CNS (N=17) or systemic (N=1) disease) and 18 (26%) had SVRL (9 primary CNS lymphomas, 9 systemic at diagnosis, among which 4 were primary testicular lymphomas). Unilateral intraocular involvement was observed in 16 (23%) cases. Clinical characteristics are reported in Table I. At diagnosis, patients received a systemic treatment in 35 (50%, including high-dose systemic MTX (HD-MTX, N 14, 20%), MTR (HD-MTX, Temozolomide and Rituximab) (N 7, 10%) and CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) with or without Rituximab (N 10, 15%)), combined systemic plus intraocular treatment in 15 (22%), local radiotherapy in 10 (14%) and intraocular therapy (intraocular injections of rituximab or MTX or steroids or a combination of these) in 9 (13%) cases. Systemic Rituximab, autologous stem cell transplantation (ASCT) and therapeutic vitrectomy/enucleation were performed in 36 (53%), 20 (29%) and 5 (7%) patients, respectively. The median number of treatments was 2 (range 0-10). Among PVRL and CVRL (N=51), median FFS, CNS relapse-free survival, eye relapse-free survival and OS were: 1.8 y, 4.9 y, 3.8 y and 4.1 y, respectively (Fig 1). Among PVRL they were: 2.6 y, not reached (NR), 5.2 y and 9.3 y, respectively. No CNS relapse occurred beyond 4 years in the PVRL subgroup. The median OS for patients diagnosed between 1990 and 1999, in contrast to 2000 and 2018 was 1.5 y vs 9.4 y respectively (p= 0.0002). OS was significantly higher in PVRL, as compared to CVRL (p= 0.04). Previous immunosuppression and poor performance status were predictive of worse outcome (p=0.04), while ASCT correlated with higher OS (p= 0.009). In PVRL, a combined systemic + intraocular therapy was associated with higher FFS (p=0.002) and CNS-relapse free survival (p= 0.003), but no difference in OS was observed. Among 18 SVRL, at a median follow-up of 1.1 y after vitreoretinal relapse, median FFS and OS were 0.3 y and 1.3 y, respectively. Systemic toxicities included 8 (11.6%) acute renal failures, 8 (11.6%) infections, and 3 (4.3%) hemorrhages. Intraocular toxicities included cataract in 11, vitreal detachment in 3 , ocular hypertension in 5, retinal vessel occlusion in 3 and keratitis in 2 cases. Of 69 patients, 39 (56.5%) died secondary to lymphoma (N=21, 53.8%), infectious toxicity (N=2, 5.2%), unrelated (N=3, 7.7%) or unknown (N=13, 33.3%) causes. Conclusions. VR DLBCL is a rare disease, which can occur as primary, concurrent with systemic, or in relapsed disease. OS over the decades has significantly improved. In PVRL, no late CNS relapses were observed, while late intraocular relapses can occur. A combined approach with intraocular + systemic HD-MTX based treatment at diagnosis was associated with a higher FFS and CNS-relapse free survival in PVRL and is recommended in bilateral involvement, even though no differences in OS were observed. Treatment consolidation with ASCT can be considered in cases with concurrent systemic disease. Further studies are needed to confirm these results and to better define the role of new drugs in treatment of this uncommon malignancy. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: PTLD is the most common malignancy, other than non-melanoma skin cancer, complicating solid organ transplantation (SOT) and has been one of the most commonly observed fatal consequences in SOT. The clinical presentations, management strategies, histologies, causes of death and outcomes are diverse (Dierickx D, Habermann TM. N Engl J Med 2018;378:549-62). The 2017 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues has redefined the categories as non-destructive PTLDs (plasmacytic hyperplasia, infectious mononucleosis, and florid follicular hyperplasia), polymorphic PTLD, monomorphic PTLD: B-cell neoplasms (diffuse large B-cell lymphoma, Burkitt lymphoma, high-grade B-cell lymphoma, plasmablastic lymphoma, plasma cell myeloma, plasmacytoma, and other) and T-cell neoplasms (peripheral T-cell lymphoma NOS, hepatosplenic T-cell lymphoma, other), and classic Hodgkin lymphoma (CHL) PTLD. We report the outcomes and long-term follow-up of patients from a single institution based on these categories whose pathology was retrospectively reviewed and reclassified based on the WHO 2017 classification. Methods: Patients with SOT who were diagnosed with PTLD at Mayo Clinic (Rochester, MN) were identified through the Mayo Clinic Lymphoma Data base and the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER). The histology was re-reviewed in 80% of the cases (RLK) and classified according to the WHO Classification of Tumours of Haematopoietic an Lymphoid Tissues 2017. Cases were considered "PTLD, unclassified" if the histology could not be confidently classified based on pathology material available for review. Indolent small B-cell lymphomas were not included among the PTLDs except for EBV-positive marginal zone lymphoma. Cox proportional hazards models were used to assess the association of clinical factors in overall survival (OS). Results: 233 patients diagnosed with PTLD between 1987 and 2017 were identified. The median age at the time of diagnosis of PTLD was 54 years (range 16 to 84) with 85 patients (36%) over the age of 60. 156 (67%) were male. The transplanted organs were kidney (41%), kidney/pancreas (5%), liver (29%), heart (9%), lung (7%), and other (8%). PTLD occurred late (more than one year after transplantation) in 66%. There were 69 stage I, 19 stage II, 8 stage III, and 128 stage IV patients. 84% presented with extranodal disease. 21% had involvement of the engrafted organ. 64% of the patients developed a PTLD that was EBV positive by in situ hybridization. Initial approaches to management included reduction of immunosuppression (N=55), chemotherapy/immunochemotherapy (N=71), reduction in immunosuppression with rituximab (N=58), single agent rituximab (N=14), and radiation therapy (N=5). At a median follow-up of 87 months (range 9-289), 139 (60%) patients had died. All six CHL-PTLD patients are alive, two of whom had an event. The median overall survival (OS) was 85 months (95% CI: 39-144) in 177 monomorphic B-cell lymphoma PTLD, 95.5 months (95% CI: 40-not reached) in 24 polymorphic PTLD, and 60 months in 8 non-destructive PTLD cases. In contrast, the median overall survival was 12 months (95% CI: 4-200) in 8 monomorphic T cell and 3 months (95% CI: 1-unreached) in 9 unclassified PTLD cases. Conclusion: PTLD is a heterogeneous group of immunodeficiency-associated lymphoproliferative disorders. The overall survival in non-destructive, polymorphic, and monomorphic PTLD were similar. Monomorphic T/NK cell types had inferior outcomes. Figure. Figure. Disclosures Maurer: Morphosys: Research Funding; Nanostring: Research Funding; Celgene: Research Funding. Ansell:Celldex: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Pfizer: Research Funding. Cerhan:Celgene: Research Funding; Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board.

Abstract Introduction Histiocytic neoplasms are rare hematological malignancies that have protean clinical manifestations and can pose significant management challenges. Recently, vemurafenib was approved by the US-FDA for treatment of BRAF-V600-mutant Erdheim-Chester disease (ECD). However, there is a lack of FDA-approved therapies for other histiocytic neoplasms such as Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD). Over the last 5 years, immune checkpoint inhibitors such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have shown significant improvement in outcomes among patients with several hematological and solid organ malignancies. In order to identify appropriate treatment candidates for these therapies, predictive biomarkers have been developed in various cancers. Evidence from solid tumors has suggested a favorable response to checkpoint inhibitor therapy with higher tumor mutational burden (TMB), defined as the number of mutations within a tumor genome. Next generation sequencing (NGS) of various tumors has shown an association between TMB of < 5 mutations/megabase (mut/Mb) to be associated with an absence of benefit from checkpoint inhibitors. In addition, high levels of PD-1/PD-L1 expression and microsatellite instability (MSI) are also correlated with response to therapy. The latter may be a result of somatic or germline alterations in DNA mismatch repair genes. In this study, we report the results for these biomarkers using NGS in patients with histiocytic neoplasms. Methods We utilized TempusTM NGS platform to analyze the tissue specimen of patients with histiocytic neoplasm. The Tempus xO Assay (Tempus Labs; Chicago, IL) combines a 1,711 gene targeted somatic and germline DNA sequencing panel with RNA-sequencing to detect both germline and somatic single nucleotide polymorphisms, indels, copy number variants, and gene rearrangements causing chimeric mRNA transcript expression in a wide array of solid tumor types. The assay utilizes formalin-fixed paraffin-embedded tumor samples and matched blood samples. TMB was calculated and reported as somatic mutations in tumor tissue per million base-pairs or mut/Mb. RNA sequencing was utilized to assess for PD-L1 and PD-1 gene expressions as compared to matched tumor and normal reference sets. Both PD-L1 and PD-1 gene expressions were reported as percentiles. DNA mismatch repair status was predicted by analysis of alterations in five common mismatch repair genes in somatic and germline DNA (MSH2, MSH6, MLH1, PMS2, and EPCAM). If there were no alterations identified in these genes, the mismatch repair status was predicted as microsatellite stable (MSS). Results A total of 13 patients with histiocytic neoplasms were included in the study. The distribution of individual histiocytic neoplasms was as follows: RDD (n=9), ECD (n=3), and LCH (n=1). The median TMB for RDD and ECD patients was 0.17 mut/Mb. For the one patient with LCH, the TMB level was 0.51 mut/Mb. Individual TMB levels are shown in figure 1. PD-L1 and PD-1 expression levels are depicted in table 1. Compared to normal reference sets, the PD-L1 expression was elevated in one patient each with RDD and ECD, and PD-1 expression was elevated in two patients each with RDD and ECD. For both ECD patients with higher PD-1 expression, NGS also showed presence of BRAF-V600E in the tumor tissue. The LCH patient had a low level of PD-L1 and PD-1 expression. For patients where evaluation of DNA mismatch repair was feasible on the tissue specimen (n=4), none showed related somatic or germline alterations. Conclusions In our series, the histiocytic neoplasms RDD, ECD, and LCH demonstrated low levels of TMB. None of the RDD and ECD patients were found to have alterations in DNA mismatch repair genes. Other markers of immunotherapy such as PD-L1/PD-1 expression appeared to be higher in ECD patients with BRAF-V600E, but in only a small subset of RDD patients. The low TMB seen in our study suggests that these histiocytic neoplasms may be less likely to respond to immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 agents as compared to the tumors with high TMB. Disclosures No relevant conflicts of interest to declare.

Abstract Background Diffuse large B cell lymphoma post-transplant lymphoproliferative disorder (DLBCL-PTLD) represents a fatal complication after a solid organ transplant (SOT). Approximately 50% of DLBCL-PTLD can be related to Epstein Barr Virus (EBV) infection. However, the EBV status is not taken into account in the DLBCL-PTLD categorization, although increasing evidence suggests its critical role in biological, clinical and prognostic aspects of the disease. In this single center retrospective study, we compared clinical and histological features, as well as outcomes of DLBCL-PTLDs by EBV status. Methods This study focused on patients with SOT who were diagnosed with DLBCL-PTLD at Mayo Clinic (Rochester, MN). Patients were identified through the Mayo Clinic Lymphoma Data base and the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), between 1989 and 2017. The histology was re-reviewed (RLK) and classified according to the WHO Classification or Tumours of Haematopoietic and Lymphoid Tissues 2017. Cell of origin (COO) was performed by Hans algorithm. EBV RNA in situ hybridization (EBER) was performed. Cox proportional hazards models were used to assess the association of clinical factors in overall survival (OS). Results 148 DLBCL-PTLD were identified. The median age at SOT and at the time of PTLD diagnosis were 50 years (range: 15-71) and 56 years (range: 18-82), respectively. The median time to PTLD diagnosis from SOT was 38 months (range: 1-499). The types of SOT included renal (44%), liver (36%), cardiac (9%), renal/pancreas (5%), pancreas (8%), lung (7%) and multiorgan (4%). 62% were stage III-IV, 30% had elevated LDH and 67% had an IPI >1. 88% of patients presented with extranodal disease, and 16% had involvement of the grafted organ. Eighty-three (56%) cases were EBV positive. The COO information was available on 35 cases. The non-GCB subtype was identified in 24 cases and GCB subtype in 11 cases. The initial treatment was as follows: reduction in immunosuppression (12%), immunosuppression reduction with rituximab (26%), rituximab alone (5%), chemotherapy with or without rituximab (35%). Patients with EBV positive PTLD were more likely to have grafted organ involvement (20% vs. 8%, p=0.047) and late PTLD (occurring after 12 months from SOT - 60% vs. 8%, p<0.001) than patients with EBV negative PTLD. There was no association between EBV status and age, sex, stage, LDH, and extranodal site involvement. At a median follow-up of 80 months (range 9-269), 83 patients (56%) had died. The 5-year survival rate from PTLD diagnosis was 56% (95% CI: 48-65%). The median OS was 85 months (95% CI: 37-148). There was no difference in OS in patients with EBV positive PTLD (median OS=84.7 months, HR=1.21, 95% CI: 0.77-1.92) versus patients with EBV negative DLBCL-PTLD (median OS=85.4 months, p=0.41). Conclusion Our study assessed the impact of EBV status on the presentation and clinical outcome of DLBCL-PTLD in a 148-patient single-institution cohort. 56% of cases were EBV positive. EBV positivity was associated with grafted organ involvement and late PTLD diagnosis. Patients with EBV-negative and EBV-positive disease had similar survival from PTLD diagnosis. Disclosures Maurer: Celgene: Research Funding; Morphosys: Research Funding; Nanostring: Research Funding. Cerhan:Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding.

Abstract Background: Peripheral T-cell lymphomas (PTCLs) comprise a group of non-Hodgkin lymphomas (NHLs) of mature T-cell origin with generally aggressive clinical behavior. Most systemic PTCLs are treated with anthracycline-based combination chemotherapy; however, outcomes remain relatively poor for most subtypes except ALK-positive anaplastic large cell lymphoma (ALCL). We have used landmark analyses based on event-free survival (EFS) to identify clinically useful endpoints in B-cell NHLs, with EFS at 24 (EFS24) months identified to stratify overall survival (OS) in aggressive B-cell NHL. Here we examined the ability of EFS24 to predict subsequent OS in a large, multinational PTCL cohort. Methods: A cohort of newly diagnosed PTCL patients treated with curative intent combination chemotherapy regimens was assembled from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), Swedish Lymphoma Registry (SWE), and British Columbia Cancer Agency (BCCA). Subtypes included ALK-negative ALCL, angioimmunoblastic T-cell lymphoma (AITL), PTCL, not otherwise specified (NOS), enteropathy-associated T-cell lymphoma (EATL), extranodal NK/T-cell lymphoma, nasal type (ENKTL), and hepatosplenic T-cell lymphoma (HSTCL). Patients were followed based on local institution guidelines, and EFS was defined as time from the date of pathologic diagnosis to progression, re-treatment, or death due to any cause. EFS24 was defined as being alive and event-free 24 months from diagnosis. Subsequent OS was defined as time from achieving EFS24 (24 months from diagnosis) or time from progression in patients failing to achieve EFS24 (progression within 24 months of diagnosis). OS was compared to the age-, sex-, and country-matched general population using United States, Sweden, and British Columbia rate tables via standardized mortality ratios (SMR) and expected survival. Results: 775 patients diagnosed from 2000-2012 were included in the combined analysis with diagnosis by the WHO classification at the respective institutions (MER=138, SWE=422, BCCA=215). Median age at diagnosis was 64 years (range 18-89) and 63% were male. Patient characteristics are summarized in the table. 736 (95%) received anthracyline-based therapy at diagnosis. At a median follow-up of 77 months (range 1-185), 516 patients (67%) had died. The percentage of patients achieving EFS24 was similar across the 3 cohorts (MER=39%, SWE=35%, BCCA= 36%, combined=36%). Median survival after progression within the first 24 months was only 4.9 months (95% CI: 3.8-5.9), with a 5-year OS of 11% and SMR of 46.4 (95% CI: 41.8-51.3). In contrast, median survival after achieving EFS24 was not reached, with a 5-year OS of 78% (95% CI: 73%-84%). This was inferior to the expected survival of 92% in the age-, sex-, and country matched population (SMR=3.16; 95% CI: 2.48-3.98). In EFS24 subgroup analyses, more favorable outcomes were observed in younger patients (age <=60 years, N=137, 5-year survival of 91% vs. 98% expected) and in patients receiving autologous stem cell transplant in first remission (N=72, 5-year survival of 88% vs. 96% expected). Patients achieving EFS24 who were not transplanted in first remission (N=189) had a 5-year survival of 74% vs. 90% expected. Conclusions: Assessment of EFS24 stratifies subsequent outcome in PTCL. Patients with early relapse from PTCL have extremely poor outcomes. However, over one-third of patients with PTCL remain in remission two years from diagnosis after initial chemotherapy and have encouraging OS rates, although survival remains significantly worse than the matched general population. Subset analysis suggests that younger patients and patients who receive autologous stem-cell transplant in first CR have 5-year survival rates that approach 90%, though still below the expected survival of the background population. The marked differences in OS after failing or achieving EFS24 in PTCL patients suggest that this endpoint may be useful for patient counseling, as a clinical trial endpoint, and as an endpoint to assess novel biomarkers for risk stratification. Table Table. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Maurer: Celgene: Research Funding; Kite Pharma: Research Funding. Jerkeman:Mundipharma: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Celgene: Research Funding. Connors:Seattle Genetics: Research Funding; Millennium Takeda: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.