Habermann, Thomas M.

Abstract Background Recent genome wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified several associations at both HLA and non-HLA loci. However, much of HL heritability remains unexplained. Methods To identify novel risk loci, we performed a meta-analysis of 3 HL GWAS including a total of 1,810 cases and 7,879 controls. Results were replicated in an independent set of 1,163 cases and 2,580 controls, for a total of 3,097 and 11,097 cases and controls combined, respectively. participants in discovery and replication stages were of European descent. quality control and imputation we conducted a meta-analysis addressing 1,004,829 variants (λ= 1.10, λ1000= 1.03). Associations between SNP genotypes and HL risk were evaluated under a log-additive model of inheritance adjusting for sex, study center and significant principal components to control for population stratification. We performed an analysis with all HL cases and then conducted stratified analyses by histological subtype (classical, nodular sclerosis and mixed cellularity), age at diagnosis (nodular sclerosis among those diagnosed at 15- 35 years in all studies, and those diagnosed at 35 and older years in the European Study only) and EBV tumor status (negative and positive). We then used a bioinformatic approach (FunciSNP) to identify potential functional variants associated with HD risk correlated with risk loci of interest. We extracted publically available ENCODE data on biofeatures to identify potential functional motifs associated with the index SNP or correlated SNPs. Finally, we measured expression levels of the two alternative mRNA transcripts in lymphoblastoid cell lines (LCLs) from 49 post-therapy HL patients and 25 unaffected controls. RT-PCR was carried out in triplicate. Relative expression levels were calculated relative to TBP as housekeeping gene. Linear models were used to assess correlation between genotype and TCF3expression levels. Results The meta-analysis identified a novel susceptibility variant at chromosome 19p13.3 (rs1860661) associated with HL risk (Odds Ratio [OR]= 0.78, P=2.0*10-8, I2=0%). variant is located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment. was also significantly associated with HL (OR= 0.85, P=0.002) in the replication series of 1,281 cases and 3,218 controls. the combined analysis consisting of the discovery and replication sets, rs1860661was strongly associated with HL (OR=0.81,=3.5*10-10), with no evidence of heterogeneity between contributing studies (Phom=0.41, I2=0%). The number of G alleles defined by rs1860661 was significantly associated with a reduced risk of each HL subtype except EBV positive HL. rs1860661 and two correlated SNPs, rs10413888 (r2=0.90) and rs8103453 (r2=0.89) identified by FunciSNP analysis map in or near marks of open chromatin and in DNAse hypersensitivity sites in TCF3 in CD20+ B cell lines., the protective minor alleles of these SNPs as defined by the G-G-G haplotype map to the binding sites for ZBTB7a (rs10413888 and rs1860661) and (rs8103453) transcription factors, likely improving the binding efficiency to the sites which may result in increased transcription rates of TCF3. TCF3 is encoded by two alternative transcripts (E12 and E47). Higher expression levels of TCF3-E47, whose transcription start site is located close to rs1860661, was associated with the rs1860661-G allele in controls (P=0.02), but not in HL patients (P=0.22). Conclusion/Discussion TCF3 is essential for the commitment of lymphoid progenitors to both B-cell and T-cell lineage development. A molecular and phenotypic hallmark of classical HL is the loss of the B-cell phenotype in HRS cells, including lack of demonstrable B-cell receptor and most B-cell specific markers such as CD19 or CD20. HRS cells have a low level of TCF3, particularly homodimers of the isoform E47, due to expression of the ABF-1 and ID2 inhibitors that bind to TCF3. Thus, higher TCF3 levels in HRS precursor cells may lead to enhanced retention of the B cell phenotype, thereby conferring a protective effect. These data suggest a link between the 19p13.3 locus including TCF3 and HL risk, indicating that TCF3 could be relevant to HL etiology and pathogenesis. Disclosures: Link: Genentech: Consultancy; Millenium: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy.

Background Burkitt NHL (BL) is a rare hematologic malignancy that occurs in younger adults and is highly curable with aggressive chemoimmunotherapy induction regimens. Unfortunately, patients that are refractory or relapse after these regimens fare poorly and treatment guidelines are not well established. The typical approach is with standard platinum-based salvage regimens; those who obtain a complete remission (CR) become eligible for autologous or allogeneic stem cell transplantation (SCT). Chimeric antigen receptor T (CAR-T) cell therapy and bispecific antibodies offer potential novel approaches for these patients, especially those who are unable to achieve remission in order to proceed with SCT; however, CAR-T therapy is not approved nor even tested in BL other than promising single case reports (Avigdor A, Bone Marrow Transplant. 2018 May 24). The goal of this study was to learn the clinical features and outcome of R/R BL in order to design a prospective strategy for novel therapy use in relapsed/refractory (R/R) BL patients. Methods We reviewed the Mayo Clinic Lymphoma database to find cases of BL diagnosed and treated between 1/1/2000 - 9/30/2018. Forty-two cases were identified and 32 (76%) entered CR and never relapsed; 10 (24%) did not respond or relapsed and are the focus of this report. Demographic, clinical response to treatment regimens, and long-term outcomes were extracted from the Mayo Clinic electronic medical record. Results The 10 patients with R/R BL had a median age of 41 years (range, 28-59); all had received aggressive chemoimmunotherapy induction regimens; 7 were primary refractory and 3 relapsed within 3 months (2-4) of achieving first CR. All 3 patients that relapsed did so in the central nervous system (CNS) despite receiving CNS prophylaxis with their induction therapy regimen. The response to salvage therapy was 30% (3/10) with 10% CR and 30% (3/10) proceeded to autologous SCT (no patients made it to allogenic SCT). The median progression free survival (PFS) and overall survival (OS) from diagnosis of all 10 patients was 4 months (1-9) and 70% (7/10) died within 6±4 months from date of relapse. The 3 patients with relapsed BL survived 7, 10, and17 months from date of relapse. The 3 patients who did survive to receive a SCT lived 2, 4, and 13 months from date of SCT. None of the 10 patients survived past 26 months from date of diagnosis. Conclusions Patients with R/R BL represent an uncommon and unique subset of aggressive NHL that require a new therapeutic approach such as CAR-T. Our study demonstrates the very poor outcome with traditional salvage therapies and the very short OS of these young, otherwise healthy patients. We recommend that these patients be considered as emergencies and referred promptly for novel therapies such as CAR-T trials at the very first sign of treatment failure. Waiting with the intent of attaining response to traditional therapies is futile. Insurance approval initiation and harvesting of T-cells should be rapidly performed, preferably prior to initiating salvage therapy, given the rapid clinical deterioration and demise of these patients. Disclosures Kenderian: Lentigen: Research Funding; Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Bennani:Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Background: Neurolymphomatosis (NL) is a highly rare disorder defined as infiltration of peripheral nervous system by a lymphoproliferative neoplasm, both presented as the first manifestation of the malignancy (primary NL) or as a site of disease progression or relapse (secondary NL). Due to rarity of this disorder data on clinical features, best approach and outcome are limited. Furthermore diagnosis of this disease is often uncertain and based on radiological images only. Methods: We retrospectively reviewed clinical records of all histologically confirmed-NL, diagnosed and treated at the Division of Hematology of Mayo Clinic in Rochester, MN between January 2002 and December 2018. Clinical features and outcome were analyzed. Responses to therapy were assessed by post-treatment radiological changes and clinical symptoms improvement. Survival analysis such as progression free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier curves with log-rank test. Comparison between subgroups was investigated using Fisher's exact test and Wilcoxon test for categorical and continuous variables, respectively. Results: Over a 16-year period 40 patients with biopsy-proven NL were included in study. Primary and secondary NL were 19 (48%) and 21 (52%) respectively, with a median age of 60.5 years (range 37-83) and male sex 24/40 (60%). The predominant histology was represented by B-cell lymphomas (39/40, 97%) with a vast majority large B-cell lymphoma (LBCL) 27/40 (67%) and only 1 case of T-cell lymphoma. The affected structures included brachial plexus (12/40, 35%), lumbosacral plexus (5/40, 12%), cauda equine and nerve roots (14/40, 35%), sciatic nerve (12/40, 30%), femoral nerve (4/40, 10%), cranial nerves (8/40, 20%), multiple nerves involved in 23/40 (57%). Four out of 40 cases had brain involvement and cerebrospinal fluid (CSF) was positive in 7/29 (24%). NL clinical manifestations included muscular weakness (33/4, 82%), sensory deficit (32/40, 80%), pain (28/40, 70%) and autonomic dysfunction (3/40, 7%). Magnetic resonance imaging (MRI) detected neural abnormalities in 35/36 cases (97%), CT imaging identified disease in 3/8 (37%) and FDG-PET scan was positive in 22/31 (71%); electromyography showed some grade of neuropathy in 28/29 (97%). Treatment included systemic chemotherapy in 38/40 (95%) cases, containing high dose methotrexate (HD-MTX) in 26/40 (65%) and rituximab in 20/40 (50%); 11/39 (28%) patients underwent consolidative autologous stem cell transplant (ASCT); 4/40 received consolidative radiotherapy (RT), 1/40 was treated with RT alone; intrathecal chemotherapy was infused in 1/40 cases; one patient with solely great auricular nerve NL involvement was cured with surgery only. Treatment efficacy evaluated by imaging and clinical improvement consisted with an overall response rate (ORR) of 73% (27/37) with a 24% (9/37) of complete remission (CR); No statistical difference in rate of response was observed by different systemic treatments. Of note, patients undergoing HDC-ASCT consolidation obtained 100% of ORR (n=10) versus 61.5% (n=16) achieved by others (P=0.03). With a median follow up of 45.1 months (range 0.5-186.7) a 36 months-OS of 77% (95% CI, 60-88) was observed for the whole cohort. A trend of longer survival rate for primary NL was observed, with a 36-month OS of 95% (95% CI, 72-99) vs. 55% (95% CI, 30-77) for secondary NL (p 0.134). A strong benefit in terms of outcome was observed for patients receiving rituximab-containing regimens with a 36 months-PFS of 72% (95% CI, 55-92) vs 28% (95% CI, 12-53) (P=0.001), and a 36 months-OS of 87% (CI 95%, 60-98) vs. 65% (95% CI , 41-84) (P=0.04) (figure 1); no survival difference was observed for patients treated with systemic therapy containing HD-MTX vs. others. ASCT consolidation was associated with a trend of improved survival with a 36 months-PFS of 69% (95% CI, 35-90) vs. 47% (95% CI, 29-66) for others (P=0.09). Conclusions: With the limit of a retrospective analysis, LBCL represent the predominant histologic subtype of NL; MRI and FGD-PET appeared to be the most accurate radiological tools to detect neural disease. Systemic treatments including rituximab should be preferred, HD-MTX seems to be not so effective while ASCT consolidation may be considered in selected patients. Due to the spare number of cases treated with RT its role cannot be clarified by our study. Disclosures Nowakowski: NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees.

Background: Central nervous system (CNS) involvement by peripheral T cell lymphoma (PTCL) is a rare condition. Among primary CNS lymphomas, only 2% are secondary to PTCL, while the risk of CNS relapse in all cases of PTCL is estimated at 2% to 6%. Little is known about the presentation and outcomes of PTCL patients with CNS involvement given the rarity of this entity. In this study, we describe patient characteristics, histology, and clinical course of patients with CNS involvement by PTCL. Methods: The Mayo Clinic Lymphoma Database was used to identify PTCL patients with primary or secondary CNS involvement seen at our institution between 2000 and 2018. A total of 12 patients were identified and their medical records were reviewed for patient and disease characteristics, CNS-directed treatment modality, and outcomes. The Kaplan-Meier method was used for time-to-event analysis. Results: The median age at CNS diagnosis was 63 years (range 41 to 76) and 11 (93%) patients were male. The histological diagnoses were PTCL, NOS in 9 (75%) patients, enteropathy-associated T-cell lymphoma in 2 (17%) patients, and angioimmunoblastic T-cell lymphoma in 1 (8%) patient. Five patients presented with primary T-cell CNS lymphoma (all with a PTCL, NOS histology), while the remaining 7 (58%) patients also had systemic involvement. All patients presented with neurologic symptoms at the time of CNS involvement diagnosis including: focal motor deficits in 6 patients (unilateral upper extremity weakness, gait impairments, and hemiparesis), cognitive decline in 5 patients (memory impairments, reduced attention, and confusion), headache in 4 patients, and seizure in 3 patients. The CNS disease location included the brain parenchyma in 9 (75%) patients, leptomeninges in 1 (8%) patient, and lumbar plexus in 1 (8%) patient. One patient (8%) had positive CSF finding only without radiologic evidence of involvement. CSF analysis was performed in 11 patients. Elevated protein levels were noted in 3 (27%) patients, malignant cells in 2 (18%), and no clear abnormalities in the remaining 6 (55%) patients. Concomitant bone marrow involvement was seen in only 1 patient. Elevated LDH was seen in 2 patients. The a median LDH was 195 U/L (range 139 to 4,360) The most common CNS-directed therapies were: high-dose methotrexate (MTX)-based regimens in 8 (67%) patients, including high-dose MTX in combination with temozolomide (n=2), or cytarabine and thiotepa (n=2). Intrathecal MTX, temozolomide and dexamethasone, lenalidomide, high-dose steroids, and surgical resection were the treatment modality used for one patient each. At a median follow up of 18 months, eight (75%) out of 12 patients were not alive at the time of last follow up. The median overall survival (OS) from diagnosis was 16 months (95% CI: 2.8-173). The median progression free survival (PFS) from initiation of CNS-directed therapy was 9 months (95% CI: 1.6-33) (figure). Four patients had a PFS longer than 12 months. These 4 patients were treated with: temozolomide/dexamethasone, high-dose MTX, lenalidomide, and high-dose MTX followed by cytarabine/thiothepa. Conclusion: CNS involvement by T-cell lymphoma is a rare complication that carries a poor prognosis. Early onset of neurologic symptoms should trigger prompt investigation of CNS involvement. Despite the short OS and PFS, some patients may achieve a relatively longer disease free interval. Disclosures Bennani: Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding. Paludo:Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding.

Introduction: Non-endemic Burkitt lymphoma (BL) is a rare and highly aggressive B-cell malignancy, of whom a substantial number are adolescents and young adults (AYAs). In this particular group of patients, the balance between efficacy and long-term toxicities is of major concern, due to the long expected remaining lifetime. In this study, we investigated the outcomes for AYA patients treated with intensive immunochemotherapy. Patients and methods: Patients were identified through queries to clinic based and population-based lymphoma registries from six countries (Australia, Canada, Denmark, Norway, Sweden, and USA). All diagnoses were confirmed by local investigators; patients with classical BL histology plus detectable MYC translocation, were included. Patients between 18 and 39 years of age at diagnosis treated with intensive immunochemotherapy (DA-EPOCH-R or more intensively) were evaluated in pre-specified age groups. All treatment protocols included rituximab. Overall survival (OS) was defined as the time from diagnosis until death from any cause or censoring, while event-free survival (EFS) was defined as the time from diagnosis until unplanned re-treatment, progression/relapse, death, or censoring, whichever came first. Response evaluation was assessed using established response criteria based on CT and/or PET/CT imaging. Survival curves were computed using the Kaplan-Meier estimator. The cumulative incidence of relapse in patients reaching complete remission (CR) or CR unconfirmed (CRu) was computed by Aalen-Johansen estimator. The 5-year restricted loss of lifetime (RLOL) was defined as the area between the patient and general population survival curves until 5-years. The general population survival was retrieved from publicly available lifetables stratified on age, sex, calendar year, and country. Results: In total, 108 AYA BL patients were included. The median age was 30 years, ranging between 18 and 39 and 82% were male. The majority had advanced stage disease (Ann Arbor stage III-IV, 76%), extranodal involvement (87%), and elevated LDH (67%). Seven patients (6%) had CNS involvement at the time of diagnosis. The chemotherapy regimens used were CODOX-M/IVAC (51%), BFM/GMALL (34%), hyper-CVAD (7%), DA-EPOCH (5%), and others (3%). Among 74 patients for whom data on tumor lysis were available, 10 (14%) developed clinical tumor lysis upon start of chemotherapy, all presenting with advanced stage and extranodal disease. The response rate was 91% (89 in CR/CRu and 2% in partial remission). At a median follow-up of 53 months, 15 had an event and 10 died. The 2-year OS and EFS for the total population was 92% (87-97%, Figure 1) and 88% (82-94%), respectively. For 13 patients aged 18-21 2-year OS and EFS were both 100%, while 2-year OS and EFS for 43 patients aged 22-30 were 98% (93-100%) and 93% (85-100%), respectively. The 2-year OS and EFS for patients aged 31-39 were 86% (76-96%) and 80% (69-91%), respectively. For patients in CR/CRu and available date of response evaluation, the 2-year post-remission OS was 99% (97-100%) and the 2-year relapse risk was 2% (0-5%), with no relapses after 6 months. Compared to the general population, the RLOL was 0.8 months (-0.5-2.2 months). Nine patients did not respond to primary treatment (SD or PD), all which belonged to the age group 31-40 years (P<0.001 versus age group 18-30 years). The oldest age group had an inferior OS compared to younger patients (P=0.008), largely due to non-responders having poor subsequent survival with a 1-year OS of 33%. Conclusion: The outcomes of AYA BL patients following intensive immunochemotherapy are excellent with high remission rates and low risk of relapse in general. However, even among young patients age remained prognostic, with patients 31 years or older having inferior OS and lower response rate to first-line treatment. In patients achieving CR, survival was similar to that of the general population over the median follow-up of 4.5 years, illustrating the need to focus on survivorship issues in these individuals. Figure 1: Overall survival for BL patients following intensive immunochemotherapy for all patients and for age groups (18-21, 22-30, and 31-39 years). Figure 1 Disclosures Jørgensen: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Holte:Novartis: Honoraria, Other: Advisory board. Molin:Roche Holding AG: Honoraria; Merck & Co., Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria. Ekstroem Smedby:Takeda: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Janssen Cilag: Honoraria, Other: Grant funding, Research Funding. Song:Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria. Cheah:Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel expenses; Celgene, Roche, Abbvie: Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

BACKGROUND: Historically, one in five Hodgkin Lymphoma (HL) patients treated with bleomycin develop bleomycin pulmonary toxicity (BPT), a life-threatening interstitial pneumonitis. The current treatment paradigm consists of prompt discontinuation of bleomycin, administration of corticosteroids, antibiotics, hospital admission, respiratory therapy, or intensive care. BPT represents a challenge for patients with HL as it not only impairs respiratory function, but also has negative impacts on clinical outcomes. A collection of a dozen studies suggest BPT has a mortality rate just short of 10% of patients who develop BPT. Given recent data on bleomycin omission with negative interim PET scan, we assessed changes in BPT rates and severity over the past 15 years. Overall, treatment protocol characterization and patient characteristics most responsive to BPT treatment are poorly understood. OBJECTIVES: In this study, we investigated the clinical impact and treatment strategies in patients with BPT. Our goals were to: 1) Identify HL patients in the last decades who developed BPT and identify risk factors for BPT, 2) evaluate the impact of BPT on long-term clinical outcomes, and 3) characterize patterns of treatment strategies among patients with HL who develop BPT. METHODS: A single-center, retrospective analysis was preformed using patient data from the Mayo Clinic Lymphoma Database (Rochester, MN) consisting of 1,299 patients diagnosed with HL. All patients were diagnosed between 2003-2018. Inclusion criteria included 1) newly diagnosed, biopsy proven HL, 2) upfront treatment with ABVD, 3) treatment was received at our institution. All patients were assessed for clinically relevant HL characteristics including stage of disease, presence of bulky disease, presence of B symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, BPT risk factors, and bleomycin treatment regimen. BPT was clinically defined as 1) Presence of pulmonary symptoms, 2) bilateral interstitial infiltrates on imaging, and 3) no evidence of infectious etiology. Patients treated in the "Early Era" (2000s) were compared to patients in the "Recent Era" (2010s). Comparison of continuous variables between BPT groups was assessed with Wilcox rank-sum test. OS and PFS were estimated via the Kaplan-Meier method. Approval of the protocol by the Mayo Clinic Institutional Review Board (IRB) was obtained and all patients were consented accordingly. RESULTS: One-hundred twenty six patients met the inclusion criteria for this study. Median follow-up for PFS and OS was 5.5 years (95%CI = 4.8-6.4) and 5.8 years (95%CI = 5.0-7.0), respectively. The 10-year OS and PFS among all patients were 85.1% (95%CI = 77.8-93.1) and 86.3% (95%CI = 80.1-93.0), respectively. Forty-seven patients (37% of all patients) met criteria for BPT. The estimated 10-year OS for BPT and non-BPT patients were 74.7% (95%CI = 61.8-90.5) and 91.7% (95%CI = 83.9-100.0), respectively. The estimated 10-year PFS for BPT and non-BPT patients were 84.7% (95%CI = 74.8-95.8) and 87.0% (95%CI = 79.1-95.8), respectively. In univariable analysis, BPT negatively impacted OS (HR=3.6, 95%CI: 1.2-10.6). However, bleomycin omission did not impact OS (HR=1.3, 95%CI=0.5-3.7). BPT-mortality was 17%. In multivariable analysis, BPT was not significantly associated with OS after adjusting for baseline characteristics (HR=3.0, 95%CI=0.9-9.9). Patients were older (median: 46 vs 33 years) and received less bleomycin (median: 107 vs 215 units) compared to non-BPT patients. BPT was most often managed with bleomycin omission with 59% of patients (74 of 126 patients) having omitted bleomycin at some point during treatment. Patients treated in the "Recent Era" (2010s) had lower BPT rates (28% vs 48%), mortality (10% vs 21%), bleomycin dose (143 vs 204 units), and bleomycin cycles (7 vs 12 cycles), yet higher prophylactic bleomycin omission (59% vs 8%) compared to "Early Era" (2000s). Patients treated in the Recent Era compared to Early Era had a reduction of BPT treatment with steroids, hospital admission, respiratory therapy, and ICU admission by 12%, 22%, 14%, 13%, respectively. CONCLUSION: Overall, our data suggests BPT continues to impact OS in HL patients treated with ABVD, however BPT treatment is decreasing as management changed in recent years. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding.

Background: While there is evidence in the literature of increased prevalence of hypogammaglobulinemia in chronic lymphocytic leukemia (CLL), there are no studies evaluating the prevalence of hypogammaglobulinemia in newly diagnosed diffuse large B cell lymphoma (DLBCL) or the relationship between hypogammaglobulinemia and presentation or outcomes. The objective of this study was to examine the prevalence of hypogammaglobulinemia in newly diagnosed DLBCL patients and to test the hypothesis that DLBCL patients with baseline hypogammaglobulinemia have a distinct clinical profile and outcome. Methods: We obtained banked frozen sera from 200 newly diagnosed, treatment-naïve, DLBCL patients from the Lymphoma SPORE Molecular Epidemiology Resource (MER), a prospective cohort study conducted at the Mayo Clinic and the University of Iowa. IgG/A/M levels were measured using immunoturbidimetric assay whereas IgE level was measured using electrochemiluminescence immunoassay; deficiency was defined using standard reference ranges. IgE levels were considered deficient if &lt;2 UI/ml. The associations between Ig deficiencies and clinical factors were evaluated with Wilcoxon rank sum and chi-squared (Fisher's exact, where appropriate) tests. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death, and EFS24 was defined as EFS at 24 months after diagnosis (achieve or failure to achieve EFS24). The association of Ig levels with EFS24 was estimated using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression, and with EFS, overall survival (OS), and lymphoma-specific survival (LSS) was estimated using Kaplan-Meier curves and hazard ratios (HR) and 95% CI from Cox regression. Results: The mean age (SD) of the cohort was 65.6 (13.4) years, 54% were males and 98% of the patients were white. Over a median follow-up of five years, there were 59 (29.5%) deaths. The prevalence of hypogammaglobulinemia, defined as any deficiency, in newly diagnosed, treatment-naïve DLBCL was 22.1% (44/199) in our cohort, and the most common Ig deficiency was for IgG (&lt;700 mg/dL, 13.5%), followed by IgM (&lt;40 mg/dL, 9.0%), IgE (&lt;2 UI/ml, 7.5%) and IgA (&lt;70 mg/dL, 4.0%) (Table1). There were no statistically significant differences between Ig deficient and non-deficient patients in terms of age at diagnosis, gender, stage, cell of origin, or MYC double hit status. However, median LDH levels were higher in Ig deficient patients (228 vs 194, p&lt;0.01). Any immunoglobulin deficiency was associated with inferior EFS (HR 1.94, 95% CI 1.16-3.24) (Figure 1) and OS (HR 2.02, 95% CI 1.17-3.49), and these associations were not attenuated after adjustment for the international prognostic index (IPI). Any Ig deficiency was also associated with failure to achieve EFS24 (OR=2.13, 95% CI 1.00-4.60) after adjusting for IPI. Conclusions: To the best of our knowledge, this is the first study to report the prevalence of hypogammaglobulinemia in treatment naïve DLBCL. We found that any Ig deficiency was not uncommon in our cohort and it was associated with an inferior EFS and OS in DLBCL patients. The prevalence of hypogammaglobulinemia in DLBCL patients seems to be lower than has been described in CLL patients. While the underlying relationship between these two immunologic disorders deserves further study, our findings highlight the interaction between global immune dysfunction and emergence of a clonal B cell process. Disclosures Nowakowski: Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Introduction: Waldenström macroglobulinemia (WM) is characterized by circulating monoclonal IgM and bone marrow infiltration with lymphoplasmacytic lymphoma (LPL) cells. Presently, there is limited data to guide prognosis or treatment options of WM based on the proportion of lymphocytes or plasma cells in the LPL population on the pathology. In this study, we aim to look at differing clinical features and outcomes of patients with WM based on the plasma cell (PC) percentage in the diagnostic bone marrow biopsy. Methods Patients with WM seen at Mayo Clinic, Rochester, MN between January 2001 and December 2017, with a bone marrow biopsy and a corresponding serum free light chain (FLC) examination at diagnosis of WM were included. The percentage of lymphocytes and PCs in the marrow biopsy was determined based on morphology ± immunohistochemistry. On immunohistochemistry, CD138 and/or MUM-1 positivity was used to quantify PCs, whereas CD20 and/or PAX5 were used to quantify lymphocytes. Patients with ≥10% PC component in the lymphoplasmacytic (LPL) cells on bone marrow biopsy were considered to have WM with excess plasma cells (WMEPC), while those with &lt;10% PCs were considered to have lymphocytic WM (LWM). Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi square test or Fisher's exact test. Time-to-next therapy (TTNT) was defined as the period from initiation of first line therapy to start of second line therapy or death due to any cause before second line therapy. Time-to-event analyses were conducted using Kaplan Meier method. Results: Of 228 evaluable patients, 147 (64%) had ≥ 10% PCs in the initial marrow biopsy. The median follow-up was 3.4 years (95% CI: 2.3-4.3 years) for LWM and 4.3 years (95% CI: 3.4-4.8 years) for WMEPC (p=0.33). The baseline characteristics of WMEPC versus LWM are depicted in Table 1. Patients with WMEPC had lower bone marrow involvement by LPL (30%) compared to LWM (60%; p&lt;0.001) at diagnosis, but the rate of symptomatic hyperviscosity was higher in WMEPC during the disease course (Table 1). The TTNT was shorter for WMEPC [2.6 years (95% CI: 1.8-4.5 years)] compared to LWM [4.5 years (95% CI 3.2-8.2)], although it did not reach statistical significance (p=0.09, Figure 1). There was a trend towards shorter OS for WMEPC [Not reached (95% CI 7.2- NR)] compared to LWM [10.7 years (95% CI 7.3 -12.1 years); p=0.28], Figure 2. Of the 228 patients, 79% (n=182) had data available for systemic therapy. The rate of PR or better with frontline therapy was higher in rates in LWM compared to WMEPC (61 % vs 42% p=0.02, Table 1). Among WMEPC cohort, patients receiving either a proteasome inhibitor (PI)-based or an immunomodulatory (IMiD)-based combination as frontline therapy (n=16) had higher rates of partial response or better (68%) compared to non-PI/non-IMiD based therapy (n=114), p=0.04. Conclusion: WM with excess plasma cells at diagnosis is associated with a trend towards shorter TTNT and OS compared to WM with &lt;10% plasma cells in the lymphoplasmacytic population at diagnosis. Our preliminary data shows higher rates of partial response or better with the use of PI/IMiD based therapy, but the small cohort size limits the strength of this finding which needs to be validated externally. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria.

Background: FDG PET/CT and bone marrow biopsy (BMB) are considered standard procedures for the staging of patients with new, untreated FL. A key issue in FL is the early identification of patients who will fail early. We recently reported (Am J Hematology 2019) that the presence of ≥2 EN sites, spleen, bone or soft tissue involvement as detected by PET all predicted failure to achieve EFS24. In Hodgkin lymphoma and diffuse large B-cell NHL, PET has replaced the routine need for a staging BMB. However, there is no such evidence in FL. The goal of this study was to determine the value of FDG PET/CT in determining bone involvement in FL using BMB as the gold standard. Methods: Patients were identified using the Mayo Clinic Lymphoma Database. 548 patients with newly diagnosed FL grades 1-3A between years 2003-2016, available BMB results, and PET/CT imaging at diagnosis, were included in the analysis. The presence of bone and spleen involvement on PET/CT, SUVmax and SUVmean of the axial skeleton at L3, and BMB results were recorded and compared. Results: In all, 36% (197/548) of patients had a positive BMB, and 34% (189/548) had bone involvement detected on PET/CT. Compared to BMB, the sensitivity and specificity of PET/CT in detecting bone involvement as determined by BMB were 60% and 80%, respectively. We noted that 59 patients had focal bone involvement on PET/CT rather than a diffuse component, and found that 47% (28/59) of these patients had a negative BMB obtained in the posterior iliac crest. Excluding these patients, the sensitivity and specificity of PET/CT in detecting bone involvement were 53% and 88%, respectively (Table 1). With respect to the spleen, 29% (157/548) of patients had evidence of splenic FL involvement on PET/CT, and of these, 69% (109/157) also had a positive BMB. The sensitivity and specificity of spleen involvement on PET/CT in predicting bone involvement on BMB were 55% and 86%, respectively (Table 2). We recorded SUV data at L3 in the 439 patients who had either a diffuse pattern of bone involvement on PET/CT, or a PET/CT read as negative. We analyzed the positive and negative predictive values (PPV and NPV) of SUVmax and SUVmean at several cut-off points to determine whether axial bone SUV is reliable at determining patients with a positive or negative BMB. The NPV for an SUVmax of less than 2.0 was 96% (n=25 patients classified as negative). For SUVmean, the best cut-off point was at less than 1.4, where NPV was 100% (n=15 patients classified as negative). There was no logical cut-off point for a significant PPV > 95%. Conclusion: In newly diagnosed FL, the sensitivity and specificity of bone involvement on PET/CT are insufficient for PET/CT to routinely replace BMB. However, in patients where the need for BMB at staging is being debated, certain factors on PET/CT can help facilitate this decision. The detection of focal bone lesions, especially those that may be missed on posterior iliac crest BMB, can make BMB unnecessary. If both the spleen and bone appear involved on PET/CT, this confers a relatively high chance that BMB will be positive. If SUVmax at L3 is less than 2.0, or if SUVmean is less than 1.4, the BMB will likely be negative, with a NPV > 95%. This decision-making algorithm is outlined in Figure 1 and may serve as a useful guideline for clinical trials and routine practice. Disclosures No relevant conflicts of interest to declare.

Acute kidney injury (AKI) is common in those with newly diagnosed hematologic malignancies. Precipitants of AKI in this population may include tumor lysis syndrome, hypotension and other insults associated with acute illness. In a general population, AKI not only leads to short-term consequences like fluid, electrolyte and acid-base abnormalities, but each episode has been linked to worse long-term outcomes, including chronic kidney disease, cardiovascular events and death. In patients with malignancies, loss of kidney function may be additionally detrimental, as this can jeopardize eligibility for full dose or first line chemotherapy, transplantation or enrollment in clinical trials. The purpose of this study is to determine the impact of AKI on long-term loss of kidney function in patients newly diagnosed with aggressive lymphomas or acute leukemia. We performed a population-based cohort study using data from the Rochester Epidemiology Project (REP). The REP is a medical-record linkage system that integrates data for patients across multiple medical care providers in Olmsted County, MN and surrounding areas to facilitate long-term follow-up. Adults admitted to the hospital between 2005 and 2017 following a new diagnosis of acute leukemia or aggressive lymphoma were evaluated for the exposure of AKI. AKI was defined by the KDIGO serum creatinine (SCr) criterion (Stage 1: 1.5-fold increase from baseline or 0.3mg/dL increase in 48-hours; Stage 2: 2-fold increase from baseline; Stage 3: 3-fold increase from baseline, increase in SCr to >4mg/dL, or initiation of renal replacement therapy). Only the first episode of hospitalization was included. Cox proportional hazards regression was used to compare the primary outcome of loss of kidney function within 12 months of hospitalization [defined as ≥30% decline from baseline estimated glomerular filtration rate (eGFR)] in those with and without AKI. A subgroup analysis was performed in patients with a baseline eGFR <60 mL/min/1.73m2. eGFR calculations used the Chronic Kidney Disease Epidemiology Collaborative equation. Outcome evaluation began 90-days after hospitalization to establish chronicity and was defined only by outpatient SCr values. Within the REP cohort, 1,085 patients were hospitalized following a new diagnosis of acute leukemia or lymphoma who consented to the use of their medical records for research. Sixteen patients with pre-existing end-stage renal disease were excluded, leaving 1,069 included patients for analysis. The majority were white (n=1,002; 93.7%) males (n=624; 58.4%) with a mean (SD) age of 64 (18) years. Mean baseline SCr was 1.0 (0.4) mg/dL with a corresponding eGFR of 80 (27) ml/min/1.73m2. A total of 355 patients (33.2%) experienced AKI during the index hospitalization, most commonly a maximum stage of I (n=231; 21.6%). Stages II and III AKI occurred in 42 (3.9%) and 59 (5.5%) patients, respectively. Cumulative incidence of ≥30% loss of baseline eGFR in the 12 months following hospitalization was 67.9% (95% CI 56.8%-76.1%) for those with any AKI and 38.8% (95% CI 31.8%-45.1%) for those without AKI during the index hospitalization. Patients diagnosed with any stage AKI were more likely to experience this outcome compared to those without AKI (HR 2.6, 95% CI 2.2-3.5, p<0.001) in unadjusted analysis. Amongst those with a baseline eGFR ≤60 ml/min, no significant difference in the outcome was noted (HR 1.7, 95% CI 0.83-3.35, p=0.15). Patients with AKI during initial hospitalization following a new diagnosis of acute leukemia or aggressive lymphoma were significantly more likely to experience ≥30% loss of baseline eGFR in the 12 months following diagnosis. This highlights a critical need to identify interventions which prevent AKI and optimize renal recovery so as to decrease overall morbidity and preserve eligibility for desirable treatment options. Disclosures Barreto: FAST Biomedical, Inc: Consultancy. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees.