ALBERT

Description: Background: Despite advances in chemotherapy, relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge and an unmet medical need. HL has a unique biology in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment. We hypothesized that using immune checkpoint inhibitor therapy to activate the immune cells in the tumor microenvironment, and concurrently targeting HRS cells with the CD30 antibody-drug conjugate brentuximab vedotin (BV), could overcome tumor cell resistance. E4412 is a Phase 1 ECOG-ACRIN sponsored study of the combination of BV and ipilimumab (IPI) and nivolumab (Nivo) in patients with R/R HL. Here we present the preliminary safety and response data on the patients treated with BV + Nivo (Arms D and E). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg and BV 1.2mg/kg (Arm D: Dose Level 1) or 1.8mg/kg (Arm E: Dose Level 2) in dose escalation with a 3+3 design and an expansion cohort (Arm F) of 9 patients. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional year (total 2 years of Nivo therapy). Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy. Patients are followed for toxicity up to 30 days beyond their last treatment. Results: As of 7/20/2016 10 patients (1 ineligible) have been treated with BV + Nivo. We report the data on the dose escalation population: 3 patients: Arm D, 7 patients: Arm E. Data will be updated to include the full BV + Nivo dose escalation and dose expansion cohorts (Arms D, E & F) (N = 19) by the time of the Annual Meeting. Median age was 46; (range: 25-53). Six patients were male. Patients were heavily pretreated with a median of 3 prior therapies. Six patients had prior SCT (5 autologous, 1 allogeneic); 2patients had prior treatment with BV. Safety: Ten of 10 patients are evaluable for safety. Overall safety profiles show that the regimen of BV + Nivo was extremely well tolerated. One patient out of 7 in dose level 2 experienced a DLT (pneumonitis grade 3 with grade 3 dyspnea and hypoxia, and typhilits grade 3), this patient had received a prior SCT, and made a full recovery from his toxicities. Per protocol he discontinued further therapy. No other DLTs were noted for the remaining 9 patients. Common and relevant toxicities considered at least possibly related to drug during any cycle of treatment are shown in Table 1. There were no Grade 4 treatment related adverse events (AEs). The only additional grade 3 AEs noted were one each grade 3 rash and puritis. The most common grade 1-2 treatment related adverse events were: transaminitis (9), peripheral sensory neuropathy (6), and rash (3). Other AEs of interest included: diarrhea (3), blurry vision (2), and myalgias (2). One grade 1-2 infusion reaction was noted, this patient was able to receive subsequent therapy with pre-medication. Response: Eight of 10 patients are evaluable for response. One patient is not yet evaluable. For the 8 evaluable patients the overall response rate (ORR) for the combination of BV + Nivo was 100%, with a CR rate of 62.5% (5/8), with 95% CI of 0.25-0.91. One patient was ineligible for laboratory studies that were out of range at screening, however this patient continues on therapy, and also had a response. One of 5 CRs occurred at in dose level 1 (BV 1.2 mg/kg). Both patients who had been treated with prior BV achieved CRs. The progression free survival (PFS) to date is 100% with a median follow-up of 0.3 years. Conclusion: In this first reported study of the combination of the checkpoint inhibitor Nivo and the ADC BV therapy was well tolerated with one DLT, and primarily grade 1 and 2 toxicities. In a heavily pretreated patient population, 20% of whom had had prior BV and 60% of whom were s/p ASCT, the ORR of 100% and CR rate of 62.5% suggests a deepening of response compared to either therapy alone. Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + Nivo, and BV + Ipi + Nivo. Data will be updated to include the full BV + Nivo cohort (N = 19) by the time of the Annual Meeting. Disclosures Diefenbach: Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Genentech: Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Molecular Templates: Research Funding; Oncomed: Research Funding; This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Hong:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Cohen:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Stanford University: Employment; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Honoraria; Sutro: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Kura: Research Funding; Merck: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Pharmacyclics: Research Funding; Infinity: Research Funding; Millennium: Research Funding; FortySeven: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Ansell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Description: Introduction: Smoking is a potential risk factor for the development of non-Hodgkin lymphoma (NHL), and prior studies have reported inferior survival in tobacco users with certain subtypes of the disease (Taborelli et al, BMC Cancer, 2017; Ollberding et al, Br J Haematol, 2013). For instance, tobacco smokers with NHL had an inferior overall survival (OS) compared to non-smokers in a series of 471 patients who were managed up front with either chemotherapy (68%), radiation (27%), or observation, and this appeared to be most pronounced in patients with follicular lymphoma and in those with a 20+ pack year smoking history (Geyer et al, Cancer, 2010). The impact of tobacco use on survival specifically in patients with mantle cell lymphoma (MCL) has not been well studied. We conducted a multicenter study in MCL and evaluated the prognostic impact of tobacco use. Methods: We included patients with MCL from 12 sites who were ≥18 years old and for whom smoking status was known at the time of diagnosis. Cases were evaluated for reported smoking status at the time of diagnosis (active smoker, prior smoker, or never smoker) and standard baseline clinical prognostic data were obtained for each patient. Descriptive statistics were generated for these characteristics and were then compared across smoking status using chi-squared tests, Fisher's exact tests, or ANOVA, where appropriate. Overall survival (OS) and progression free survival (PFS) were estimated using the Kaplan-Meier method, and were compared using log-rank tests. Results: Of 946 included patients, 456 (48.2%) reported never using tobacco, 360 (38.7%) reported prior tobacco use, and 130 (13.7%) reported active tobacco use at the time of diagnosis. Median age was 59 in the active smoker group, 65 in prior smokers, and 61 in never smokers (p 〈 0.001). Any major medical comorbidity (defined as the presence of CAD, CHF, diabetes, CKD, ESRD, COPD, DVT, prior malignancy, or cirrhosis) was present in 59 (45.4%) of the active smokers, 143 (39.7%) of the prior smokers, and 140 (30.7%) of the never smokers (p = 0.002). Intensive induction regimens were used in 58.2% of active smokers, 47.2% of prior smokers, and 58.4% of never smokers (p=0.007). There were no significant differences between groups in regards to sex, race, ECOG performance status, Ann Arbor stage, time to first treatment, and use of auto transplant in first remission. Patients with no prior history of tobacco use were less likely to have a high risk MIPI score at diagnosis (26% high risk) compared to prior smokers (39.5%) and active smokers (32.5%, p=0.019). With a median follow up of 3.5 years after diagnosis, there was no significant difference between the 3 groups with regards to PFS or OS (Figure 1). Five-year OS in the never smoker group was 79.8% (95% CI: 74.8%, 83.9%) vs 75.1% (64.5%, 82.9%) in the active smoker group, and 80.6% (74.6%, 85.3%) in the prior smoker group (log rank p = 0.4079). Five- year progression free survival was 50.4% (44.6%, 56.0%) in the never smoker group, 42.5% (32.2%, 52.5%) in the active smoker group, and 50.2% (43.5%, 56.6%) in the prior smoker group (log rank p= 0.3595). Conclusions: Our data suggest that active or prior smoking does not significantly impact OS or PFS in patients with MCL. This study is limited by the fact that amount of current or former tobacco use was not available and it is not known how many current tobacco users ultimately stopped smoking during the course of their treatment. Future studies should incorporate more specific information regarding smoking history including pack-years and time between discontinuation of tobacco use and date of diagnosis. While tobacco use and other modifiable cardiovascular risk factors should be addressed as appropriate for all patients with MCL, current and former tobacco users can still achieve prolonged PFS and OS and may be candidates for intensive treatments after consideration of their other comorbidities and disease-specific risk factors. Disclosures Calzada: Seattle Genetics: Research Funding. Kolla:Amgen: Equity Ownership. Bachanova:Gamida Cell: Research Funding; GT Biopharma: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Gerson:Seattle Genetics: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding. Danilov:Celgene: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Pharmacyclics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Curis: Consultancy; Takeda Oncology: Research Funding; Seattle Genetics: Consultancy. Grover:Seattle Genetics: Consultancy. Karmali:Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau. Hill:Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghosh:Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Genentech: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; Gilead/Kite: Consultancy, Speakers Bureau; Spectrum: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; Astra Zeneca: Speakers Bureau. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Hamadani:Pharmacyclics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy; Janssen: Consultancy; Medimmune: Consultancy, Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Otsuka: Research Funding; Takeda: Research Funding. Kahl:TG Therapeutics: Consultancy; BeiGene: Consultancy; Seattle Genetics: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Martin:Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Teneobio: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy. Flowers:Karyopharm: Consultancy; Denovo Biopharma: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Spectrum: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; BeiGene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding.

Description: Abstract 687 Background: A persistently positive PET scan after just a few cycles of therapy is predictive of a poor clinical outcome in diffuse large B-cell lymphoma (DLBCL). Prior data suggested that about one third of patients remain PET positive after 2–4 cycles, with ≤ 20% 2 year progression-free survival (PFS) for such patients. A response-adapted strategy was studied in E3404 to test the hypothesis that an early treatment change to four cycles of R-ICE might reduce the treatment failure rate of patients whose PET scan remained positive after an initial 3 cycles of R-CHOP. Study Design: Previously untreated patients with DLBCL stage III, IV, or bulky II, with measurable disease, HIV negative, and with adequate organ reserve, were eligible. PET/CT scan was performed before treatment and again after 3 cycles of R-CHOP. A fourth cycle of R-CHOP was given while the scan was centrally reviewed and scored as either positive or negative for FDG-avid tumor by a single reviewer using criteria based on modifications of the Harmonization Criteria. Persistently PET-positive patients received 4 cycles of R-ICE, while PET-negative patients received 2 more cycles of R-CHOP, for a total of 6 cycles. PET/CT was performed again at the end of treatment. A ≥45% 2 year PFS for mid-treatment PET- positive patients was viewed as a promising result, with 88% power if 33 such patients were accrued. Total accrual of 99 patients was therefore planned. Results: Of 100 patients accrued, 78 were eligible; all but 1 ineligibility was based on central pathology review. Fifty-eight were male; median age was 62 years (20–74); 13% IPI 0–1, 31% IPI 2, 37% IPI 3, and 19% IPI 4–5. Seventy-four of 78 (95%) patients completed the first 3 cycles of R-CHOP. Of 72 patients continuing treatment, 67 (93%) completed protocol treatment: 83% of mid-treatment PET-positive and 93% of PET-negative patients. Of 74 patients undergoing mid-treatment PET scan, 12 (16%) were scored as positive, and 62 (84%) as negative. At the end of treatment, 13% were scored as positive, and 87% as negative. Two-year PFS, from the time of study entry, was 72% among all eligible patients. Two year PFS from the time of mid-treatment PET scan was 45% (90% CI, 21–67%) for patients scored as mid-treatment PET-positive, and 77% (90% CI 67–85%) for patients scored as mid-treatment PET-negative. The 80% confidence interval (corresponding to a test with a one-sided type I error of 10%) did not include the null hypothesis of 25%, implying that the results met the pre-specified threshold. Among all 78 eligible patients, 10 have died (13%); 5-year overall survival was 87% (90% CI 78–92%) Three-year overall survival was 67% (90% CI 40–84%) for mid-treatment PET-positive patients, and 93% (90% CI 85–97%) for mid-treatment PET-negative patients. Conclusions: The 2-year PFS for mid-treatment PET-positive patients met the threshold to be considered promising, but the confidence interval was wider than expected due to the small patient number. In addition, the inter-observer variability in the interpretation of mid-treatment PET scans as a binary variable in this study (studied and reported separately in Horning SJ et al. Blood 2010) implies that treatment modification based on early PET scanning should remain confined to clinical trials. Disclosures: Swinnen: Celgene: Consultancy; Genentech: Research Funding. Quon:Genentech: Research Funding. Advani:Pharmacyclics: Research Funding. Kahl:Roche/Genentech: Consultancy; Celgene: Consultancy; Cell Therapeutics: Consultancy; Janssen: Consultancy; GSK: Consultancy; Gilead: Consultancy. Horning:Genentech: Employment; Roche: stock, stock Other.

Description: Introduction Limited stage disease accounts for 30-40% of Diffuse Large B-cell Lymphoma (DLBCL), with better overall survival than advanced stage disease, but with increased late relapses regardless of treatment strategy (Stephens 2016). Preferred treatment for these patients (pts) per NCCN guidelines is abbreviated R-CHOP followed by radiotherapy. Based on promising results of radioimmunotherapy consolidation in SWOG S0313 (Persky 2015), and of PET-directed experience by the BC Cancer Agency (Sehn 2011), we designed a National Clinical Trials Network (NCTN) PET-directed study to tailor therapy after 3 cycles of R-CHOP, to improve outcomes and decrease toxicities. Methods Pts had non-bulky (〈 10 cm) stage I/II untreated DLBCL. Mediastinal, HIV-associated, testicular, central nervous system, and indolent lymphoma were excluded. Pts received standard R-CHOP therapy and had an interim PET scan on day 15-18 of cycle 3, which was centrally reviewed in real time. Pts with negative PET scan (Deauville 1-3, iPET-neg) proceeded with 1 additional cycle of R-CHOP. Pts with positive PET scan (Deauville 4-5, iPET-pos) initiated 36 Gy of involved field radiation therapy (IFRT), plus additional boost to FDG-avid area up to 9 Gy, within 5 weeks of 3rd cycle of R-CHOP. This was followed by ibritumomab tiuxetan (IFRT-Zevalin) 3-6 weeks after completing IFRT. Final PET scan was performed 12 weeks after treatment completion. Results The study completed accrual in June 2016. Safety, response, interim PET, and immunohistochemistry-based cell of origin (COO) and MYC/BCL2 analyses were presented previously (Persky 2017, Stephens 2017). Of 159 pts enrolled, 1 was upstaged by PET, and 26 pts were ineligible - due to incorrect histology (mostly concurrent indolent or follicular lymphoma grade 3B) (21), lack of diagnostic tissue submission for central pathology review (3), and bulky disease (2). In 132 eligible pts, median age was 62 years, 62% had stage I, 17% had B symptoms, 14% had elevated LDH, 43% had extranodal involvement, and 66% had exclusive involvement of the head and neck region. Stage modified IPI (smIPI, Miller 1998) was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the pts. COO by Lymph2Cx was assessable in 87 pts - 68% were GCB, 23% were ABC, and 9% were unclassifiable. Double protein expressers (MYC and BCL2, DPE) were 16%, while 4 (3%) pts had "double hit" lymphoma (DHL) - 2 with MYC/BCL2 and 2 with MYC/BCL6 rearrangements - none of which were DPE. Of 132 eligible pts, 128 had an interim PET scan centrally reviewed, of which 110 were iPET-neg. Only 18 were iPET-pos, 4 of them due to infection (Deauville X) which were treated as iPET-neg. Of 14 truly iPET-pos pts (11%), 2 refused radiation, and 12 pts received IFRT-Zevalin. Eight pts (67%) converted from PR to CR after IFRT-Zevalin and 4 (33%) had PR, for an overall CR of 92% and PR of 4% (with 4% unevaluable). With median follow up of 4.5 yrs (range 1.1 - 7.5 yrs), only 5 pts progressed and 2 died from lymphoma. Of 5 progressors, 3 received R-CHOP x 4, 1 was iPET-pos but declined radiation, and 1 went off treatment after 1 cycle of R-CHOP. Eleven pts died from non-lymphoma causes, including 1 pt from secondary AML (iPET-neg arm), and 1 of lung adenocarcinoma diagnosed upon iPET. S1001 5-yr PFS estimate is 87% and OS estimate is 90% (figure 1), with iPET-pos and iPET-neg pts having similar outcomes - PFS 86% vs. 88%, OS 93% vs. 91%, respectively. Five-yr PFS by smIPI was 97% for smIPI of 0, 86% for 1-2, and 30% for 3. GCB had 5-yr PFS of 95%, vs. 70% for ABC and 47% for unclassifiable. DPE pts had 5-yr PFS of 70, vs. 89% for non-DPE pts. All 4 DHL pts maintain remission. Conclusions S1001 is the largest US study of limited stage DLBCL in the rituximab era, with best NCTN results in this disease subset. Only 5 patients progressed and 2 died from lymphoma. Our study confirms the distinct biology of limited stage DLBCL, with predominance of GCB origin (68%), and head and neck location (66%). Due to small number of lymphoma events, no strong conclusions about prognostic ability of smIPI, COO, DPE, or DHL, could be made. S1001 demonstrated that 89% of pts maintained excellent outcomes after R-CHOP x 4 with PET-directed therapy. Only 11% of pts were iPET-pos and required radiation, but they also had excellent outcomes. Together with the FLYER trial in younger pts (Poeschel 2018), this NCTN trial establishes R-CHOP x 4 alone as the new standard approach to limited stage disease for majority of the pts. Disclosures Persky: Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Stephens:Acerta: Research Funding; Karyopharm: Research Funding; Gilead: Research Funding. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Bartlett:Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genenetech: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy. Barr:Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Leonard:Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Sutro Biopharma: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy. Kahl:TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; BeiGene: Consultancy. Fisher:Celgene: Consultancy; AstraZeneca: Consultancy; Barclays: Honoraria; prIME: Honoraria. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. OffLabel Disclosure: Ibritumomab tiuxetan in diffuse large B-cell lymphoma

Description: Mantle cell lymphoma (MCL) is a mostly incurable malignancy arising from naive B cells (NBCs) in the mantle zone of lymph nodes. We analyzed genomewide methylation in MCL patients with the HELP (HpaII tiny fragment Enrichment by Ligation–mediated PCR) assay and found significant aberrancy in promoter methylation patterns compared with normal NBCs. Using biologic and statistical criteria, we further identified 4 hypermethylated genes CDKN2B, MLF-1, PCDH8, and HOXD8 and 4 hypomethylated genes CD37, HDAC1, NOTCH1, and CDK5 when aberrant methylation was associated with inverse changes in mRNA levels. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a small modular immunopharmaceutical (CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the histone deacetylase inhibitor suberoylanilide hydroxamic acid in induction of the hypermethylated genes and anti-MCL cytotoxicity. Our data show prominent and aberrant promoter methylation in MCL and suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.

Description: Key Points HGBL-DH/TH makes up 8% of de novo DLBCL, with HGBL-DH/TH with BCL2 rearrangement being a GCB phenomenon. Restricting FISH testing to tumors with dual protein expression and GCB subtype results in testing

Description: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. After decades of stagnation, the natural history of FL appears to have been favorably impacted by the introduction of rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Maintenance rituximab strategies can improve progression-free survival. Even chemotherapy platforms have changed in the past 5 years, as bendamustine combined with rituximab has rapidly become a standard frontline strategy in North America and parts of Europe. Recent discoveries have identified patients at high risk for poor outcomes to first-line therapy (m7–Follicular Lymphoma International Prognostic Index [m7-FLIPI]) and for poor outcomes after frontline therapy (National LymphoCare Study). However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation. The development of targeted agents, exploiting our current understanding of FL biology, is a high research priority. A multitude of novel therapies are under investigation in both the frontline and relapsed/refractory settings. It will be critical to identify the most appropriate populations for new agents and to develop validated surrogate end points, so that novel agents can be tested (and adopted, if appropriate) efficiently.

Description: Introduction. The VES-13 is a simple, self-reported, function based tool originally developed to screen community-dwelling populations to identify persons age 65 years and older at risk of death and functional decline, including death in the next 12 months. The VES-13 items include patient's age, self-rated overall health status, functional limitations in physical activity, and functional disabilities in more complex activities of daily living. As part of the Lymphoma Epidemiology of Outcomes (LEO) cohort study, we collected self-reported VES-13 data at study enrollment on all participants regardless of age, and here we report on the prevalence of vulnerable status defined by the VES-13 and its association with 1-year mortality, overall, stratified at age 65 years, and in the subset of diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy. Methods. From 7/2015 to 6/2017, 3253 participants with NHL were enrolled within 6 months of their diagnosis into the LEO cohort. 2004 were evaluable on VES-13, and 1183 (59%) completed it before the initiation of therapy. VES-13 scores range from a minimum of 0 (low risk for decline) to a maximum of 10 (greatest risk for decline), and a score ≥3 was classified as vulnerable. Clinical, pathology and treatment data were abstracted using a standard protocol, and participants were contacted every 6 months for the first three years and then annually thereafter to identify outcomes. Medical records were reviewed by LEO clinicians to classify cause of death according to a standard protocol. Therapy was determined by the treating physician, and this was independent of knowledge of the VES-13 score. The association of VES-13 with 1-year mortality from date of diagnosis was estimated using odds ratios (OR) and 95% confidence intervals (CI) from logistic regression models, which also provided model c-statistics. Results. The median age of the 2004 participants in this analysis was 62 years (range 18-94); 57% were male; 54% were ≥65 years; and 28% had a normal body mass index (BMI), 1% were underweight, 35% were overweight, and 36% were obese. Clinically, 59% of participants had an aggressive subtype, 65% were stage III-IV, 24% had B-symptoms, and 11% had a performance status (PS) of ≥2. Overall, 28% of participants were classified as vulnerable (95% CI 26%-30%), with a higher prevalence among those completing the survey after initiation of therapy (38%, 95% 34%-41%) versus before initiation of therapy (22%, 95% CI 20%-24%), and a higher prevalence for those ≥65 years (32%, 95% CI 29%-34%) versus

Description: Key Points Plasma EBV-DNA is highly concordant with EBV tumor status in Hodgkin lymphoma. Plasma EBV-DNA has prognostic significance in Hodgkin lymphoma, both before therapy and at month 6 of follow-up.

Description: Background: Induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard of care for transplant eligible (TE) patients (pts) with untreated mantle cell lymphoma (uMCL); however, there is no consensus on the optimal induction regimen. The addition of rituximab + high-dose cytarabine (RC) to an RCHOP-like regimen is associated with better outcomes. In addition, two randomized trials have demonstrated superior efficacy and tolerability for rituximab/bendamustine (RB) compared to RCHOP for uMCL. Based on this, we conducted a phase 2 trial of 3 cycles of RB followed by 3 cycles of RC in 23 TE pts with uMCL, with encouraging preliminary results (Armand, BJH 2016). Pts continued to be followed for relapse and survival. Meanwhile, RB/RC became the standard frontline regimen at Dana-Farber Cancer Institute (DFCI). Simultaneously, investigators at Washington University in St. Louis (WUSTL) initiated a similar study of alternating cycles of RB/RC for uMCL. Herein, we report the results of both phase 2 trials as well as the off-trial experience. Methods: In the DFCI trial, TE pts (age 18-69) with uMCL were treated with 3 cycles of RB (R 375 mg/m2 d1, B 90 mg/m2 d1-2) followed by 3 cycles of RC (R 375 mg/m2 d1, C 3gm/m2 BID d1-2 with dose reductions for age, renal dysfunction, or pre-existing neurotoxicity). Off-trial pts treated with RB/RC at DFCI or in consulting community practices were retrospectively identified using clinical and pharmacy databases. In the WUSTL trial, TE pts (age 18-65) received alternating cycles of RB (cycles 1, 3, 5) and RC (cycles 2, 4, 6) (same dosing as above). Response assessments were made using CT scans for the DFCI trial and PET/CT for the WUSTL trial and DFCI off-trial pts. Results: In total, 86 pts (23 DFCI trial, 49 DFCI off-trial, 14 WUSTL trial) were treated with RB/RC. The median age was 57 (range 30-72). Pts in the WUSTL cohort were more likely to be male, have a high MIPI score, and have blastoid variant (Table). 94% of pts completed 6 cycles of RB/RC therapy. Off-trial pts were more likely to receive a lower starting dose (≤ 2gm/m2) of cytarabine (76%) compared to trial pts (38%). At the EOI, the overall response rate and CRR were 98% and 92%, respectively, with similar response rates across cohorts (Table). 73 pts (85%) subsequently underwent ASCT and 4 additional pts (5%) have ASCTs planned. 9 pts did not undergo ASCT because of persistent or PD (n=3), prolonged cytopenias (n=3), an incidentally identified ASXL1 mutation without cytopenias (n=1), pt preference (n=1), and inadequate stem cell collection (n=1). Delayed platelet engraftment after ASCT was seen for pts receiving alternating cycles of RB/RC compared to sequential RB/RC at day 30 (plts