ALBERT

Description: Background: Loss of major histocompatibility Class II antigens (MHCII) in diffuse large B-cell lymphoma (DLBCL) is associated with a decreased CD8+ tumor-infiltrating T-lymphocyte (TIL) response and poor patient survival. Transcription of the MHCII gene complex is under the control of the master transactivator, CIITA, which in part is regulated by histone acetylation. We tested the hypothesis that combination of histone deacetylase inhibitor vorinostat with standard chemotherapy will enhance MHCII expression and improve patient outcome in DLBCL. Methods: SWOG S0806 was a phase I/II open label trial of vorinostat given at 400 mg po daily on days 1-9 (subsequently reduced to days 1-5) combined with Rituximab-CHOP (R-CHOP) at standard doses, given on day 3 of a 21-day cycle for 8 cycles. Eligibility criteria included having newly diagnosed advanced stage DLBCL, international prognostic index (IPI) of at least 1, and lack of known CNS involvement or HIV. Primary endpoint of phase I was to establish maximum tolerated dose (MTD) of vorinostat with standard R-CHOP. Primary endpoint of phase II was to estimate 2-year progression free survival (PFS). Translational endpoints included correlation of pre-treatment acetylation status of histones, expression of MHCII genes, and percentage of TIL to PFS; and correlation of cytokine profile to response and outcomes. Results: Phase I was open in 5 SWOG institutions and enrolled 11 patients. There were only 2 patients who had dose limiting toxicities in the first cycle - grade 3 febrile neutropenia and grade 4 hypokalemia - allowing phase II to proceed with the original vorinostat dosing of 400 mg daily days 1-9, at all SWOG institutions. However, excess rates of febrile neutropenia and sepsis were seen upon further follow up, and the study was amended to reduce the duration of vorinostat to days 1-5. A total of 72 patients were enrolled in phase II, of which 8 were ineligible and 2 withdrew consent prior to treatment. For the remaining 62 patients, median age was 64 years, 92% had stage III/IV disease, 39% B symptoms, 61% elevated LDH, 39% had more than 1 extranodal site of involvement, with IPI breakdown of 13/26/47/13/2%. Notable grade 3-4 non-hematologic toxicities included febrile neutropenia (39%), sepsis (18%), fatigue (15%), hypokalemia (11%), hyponatremia (10%), and small bowel perforation (3%). Grade 3-4 hematologic toxicities included neutropenia (60%), anemia (35%), and thrombocytopenia (35%). There was one death in phase I from sepsis and multi-organ failure at the end of 8 cycles of treatment, but no deaths from toxicity in phase II. Overall response rate was 81% (95% CI: 69-90%). With median follow-up of 24.3 months, estimate of 2-year PFS is 72% (95% CI: 58%, 81%) and of 2-year OS is 85% (95% CI: 74%, 92%). Analysis of the panel of 30 cytokines performed on matched serum specimens of 40 patients showed correlation of baseline elevated IL-2R levels with worsened PFS and OS, and correlation of decrease in Epidermal Growth Factor level with improved PFS and OS. Results of immunohistochemical stains for expression of MHCII genes and percentage of TIL will be reported at the meeting. Conclusions: The regimen of vorinostat-R-CHOP achieved 2-year PFS estimate of 72%, which is slightly more than 68% expected from R-CHOP alone per IPI adjusted historical rate, but less than an IPI adjusted target of 78% that would be sufficient to warrant further investigation. It also resulted in unexpected excess rates of febrile neutropenia and sepsis. This regimen cannot be recommended for the broad DLBCL population. Current studies are focused on finding biomarkers of response to histone deacetylase inhibitors. Disclosures Persky: Gilead Sciences, Inc: Speakers Bureau. Off Label Use: vorinostat in diffuse large B-cell lymphoma. Barr:Abbvie: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

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: 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: Abstract 98 Background: Advanced follicular lymphomas (FL) are incurable with conventional chemotherapy and there is no consensus on the best treatment approach. The SWOG cancer research cooperative group and Cancer and Leukemia Group B (CALGB) compared the safety and efficacy of two immunochemotherapy regimens for FL in a Phase III randomized intergroup protocol (S0016) that enrolled 554 patients with previously untreated, advanced stage FL between 3/1/2001 and 9/15/2008. Methods: Pts were eligible if they had advanced stage (bulky stage II, III or IV) evaluable FL of any grade (1, 2, or 3) and had not received any prior therapy. In one arm (CHOP-R), patients received 6 cycles of CHOP chemotherapy (750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine, and 100 mg prednisone daily for 5 days) at 3 week intervals with 6 doses of rituximab anti-CD20 antibody (375 mg/m2 on days 1, 6, 48, 90, 134 and 141 according to the schedule described by Czuczman et al.[J.Clin.Oncol 17:268, 1999]). In the second arm of the protocol, patients received 6 cycles of CHOP, followed by a dosimetric infusion of tositumomab/iodine I-131 tositumomab and then 1–2 weeks later a therapeutic infusion of I-131-tositumomab labeled with sufficient I-131 (median 85 mCi) to deliver a total body dose of 75 cGy (CHOP-RIT). The study was designed to have 86% power to detect a hazard ratio (HR) of CHOP-RIT to CHOP-R of 0.67 for 2 yr PFS based on a one-sided.021 level test (accounting for 3 interim analyses). Results: Of the 554 enrolled pts, 532 were eligible and 526 were evaluable for toxicity (263 on each arm of the protocol). Pt characteristics (age, sex, race, stage, beta 2 microglobulin level, tumor bulk, B symptoms) were well-balanced in the two arms of the protocol. In general, both regimens were well-tolerated (Table I). Median follow-up time among patients still alive is 4.9 years. One hundred and six of 267 eligible pts on the CHOP-R arm have progressed or died compared to 86 of 265 eligible pts on the CHOP-RIT arm. The 2 year estimate of PFS was 76% on the CHOP-R arm and 80% on the CHOP-RIT arm (Figure 1). In multivariate Cox regression adjusting for the stratification factor (serum beta-2 microglobulin level), the hazard ratio for CHOP-RIT vs. CHOP-R was 0.79 (95% CI: 0.60–1.05, p=.11 [2-sided] or p=.06 [1-sided]). Twenty-six of 267 pts on the CHOP-R arm have died compared to 40 of 265 eligible pts on the CHOP-RIT arm. The 2-year estimate of overall survival was 97% on the CHOP-R arm and 93% on the CHOP-RIT arm. In multivariate Cox regression adjusting for the stratification factor serum beta-2 microglobulin, the hazard ratio for CHOP-RIT vs. CHOP-R was 1.55 (95% CI: 0.95–2.54, p=.08 [2-sided]). Conclusion: No statistically significant differences in PFS, OS, or serious toxicities are yet demonstrable with either regimen administered in this trial. However, PFS and OS are outstanding with either of the two regimens with median times to progression not yet reached for either treatment. Future studies will be needed to assess whether combining CHOP-R with RIT consolidation and with maintenance rituximab will confer additive benefit, as being evaluated in a follow-up trial (SWOG protocol S0801) that has recently completed accrual. Disclosures: Press: Spectrum: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Off Label Use: Front-line use of I-131-tositumomab for consolidation therapy in 1st remission of follicular lymphoma. Friedberg:Genentech: Consultancy, Honoraria. Czuczman:Glaxo Smith Kline: Consultancy, Research Funding; Genentech: Consultancy, Honoraria. Kaminski:Glaxo Smith Kline: Patents & Royalties. Maloney:Genentech/Roche: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau. Cheson:Glaxo Smith Kline: Research Funding. Fisher:Roche: Consultancy, Honoraria.

Description: Abstract 3938 The proteasome inhibitor (PI) bortezomib (BTZ) is approved for the treatment of refractory mantle cell lymphoma (MCL). However, BTZ achieves clinical responses in only 40% of refractory MCL patients, justifying the search for newer proteasome inhibitors and/or the development of rational combination regimens. Recently we reported that the irreversible PI carfilzomib (CFZ) interacted synergistically with the histone deacetylase inhibitor (HDACI) vorinostat (Vor) in diverse DLBCL cells including GC (germinal center) and ABC (activated B-cell) sub-types both in vitro and in vivo. (Dasmahapatra et al., Blood 2010; 115:4478-87, 2010). Moreover, regimens combining PIs with histone deacetylase inhibitors (HDACIs) have shown promising activity in multiple myeloma. Collectively, these preclinical and clinical findings raise the possibility combining CFZ with HDACIs might be an effective strategy in MCL. To test this possibility, CFZ/HDACI interactions were investigated in diverse MCL cell types, including those resistant to BTZ. Simultaneous treatment (24-48 hr) with sub-lethal CFZ concentrations (2-5 nM) and minimally toxic concentrations of vorinostat (Vor; 1–2 μM), SNDX-275 (1-2 μM) or SBHA (30-50 μM) strikingly increased apoptosis (manifested by annexin V, 7-AAD or TUNEL positivity) in various MCL lines, including Granta, HF-4B, Rec-1, JVM-2, MINO and JVM-12. Interactions were highly synergistic, as determined by Median Dose Effect analysis, with Combination Index values significantly less than 1.0. HDACIs also interacted synergistically with ONX 0912 (formerly PR-047), an orally bioavailable analog of CFZ. The activity of these regimens was associated with a sharp increase in caspase-3 activation, PARP cleavage, mitochondrial damage (loss of ΔΨm, cytoplasmic cytochrome c release), and induction of p21CIP1. Combined CFZ/Vor exposure also markedly induced phosphorylation of JNK and c-Jun, down-regulation of phospho-AKT and phospho-ERK1/2, and induction of γH2A.X, a marker of double-stranded DNA breaks. In contrast to single agent administration (48 hr), where the percentage of apoptotic cells gradually declined following drug washout over the ensuing 4–5 days, extensive apoptosis (e.g. 〉 80%) persisted in cells co-treated with CFZ/Vor. Combined treatment of MCL cells with CFZ/Vor induced more sustained inhibition of chymotrypsin-like (CT-L) proteasome activity than that observed following single-agent treatment. CFZ alone exhibited partial cross resistance to BTZ- resistant Granta cells (GR-25BR). However, co-administration of CFZ/Vor resulted in the highly synergistic induction of apoptosis in BTZ-resistant cells. Genetic interruption of JNK signaling (e.g., via shRNA knockdown) significantly attenuated CFZ/Vor-mediated apoptosis, indicating that JNK activation plays a functional role in the lethality of this regimen in MCL cells. Combined treatment with CFZ and HDACIs induced G2M arrest in both parental and BTZ-resistant GR-25BR cells, an effect that was not modified by genetic interruption of JNK signaling. The CFZ/Vor regimen also strikingly induced apoptosis in 3 primary human MCL specimens, in contrast to the minimal lethality exhibited toward normal CD34+ cells as previously described (Blood; 115:4478-87, 2010). Finally, in vivo administration of CFZ (IV BIW) and Vor (IP TIW) to Beige-nude-XID mice (NIH-III) inoculated in the flank with Granta cells substantially suppressed tumor growth compared to single agent treatment. Collectively, these findings indicate that combining HDACIs with CFZ synergistically induces apoptosis in MCL cells through a JNK-dependent mechanism in association with G2M arrest and the induction of DNA damage. They also suggest that this strategy, which is active against diverse MCL cell types, including BTZ-resistant and primary MCL cells, and which displays in vivo activity, warrants further examination in MCL. Accordingly, plans for a Phase I CFZ/HDACI trial in NHL, including MCL patients, are currently underway. Supported by Lymphoma SPORE 1P50 CA130805. Disclosures: Friedberg: Genentech: Honoraria.

Description: Background: Cancer is associated with thrombosis, but the frequency of thromboembolism in hospitalized cancer patients receiving contemporary chemotherapy regimens is not known. We investigated the frequency of arterial and venous thromboembolism in hospitalized cancer patients receiving active therapy (as identified by the presence of neutropenia) and characterized its association with in-hospital mortality. Methods: We conducted a retrospective cohort study using the discharge database of the University HealthSystem Consortium. This included 66,106 adult neutropenic cancer patients with 88,074 hospitalizations between 1995 and 2002 at 115 academic medical centers. Patients were identified using ICD-9-CM codes that contained at least one diagnosis of malignant disease and agranulocytosis. Patients with thromboembolism were identified using codes for venous thrombosis, pulmonary embolism, arterial embolism, acute cerebrovascular disease, and acute coronary arterial disease. The association of VTE with clinical variables was studied in univariate analysis and in a multivariate logistic regression model. The chi-square test was used to compare categorical variables, and Cochran-Armitage test to determine trend. Results: Thromboembolism was reported in 5,272 patients (8%), with 5.4% patients developing venous and 1.5% arterial thromboembolism during the first hospitalization. There was a significant association between the occurrence of venous and arterial thromboembolism (OR 1.73, 95%CI, 1.38–2.16). Venous thromboembolism was more frequent in patients with metastatic disease (OR, 1.23, 95% CI 1.13–1.34), but arterial thromboembolism was not (OR, 0.59, 95% CI, 0.51–0.69). In-hospital mortality was significantly greater in patients with venous (OR 2.01, 95% CI 1.83– 2.22) or arterial thromboembolism (OR 5.04, 95% CI, 4.38–5.79), even in patients without metastatic disease. Patients with lymphoma or leukemia accounted for one-third of venous events and one-half of arterial events. Clinical variables most frequently associated with thromboembolism in a multivariate logistic regression analysis were age ≥ 65 years, primary sites of cancer including lung, gastrointestinal, gynecologic and brain, length of stay ≥ 10 days, and comorbidities including infection, pulmonary and renal disease, and obesity. From 1995 to 2002, there was a 36% increase in venous and a 124 % increase in arterial events (P for trend

Description: An inverse relationship between BCL-2 expression and cell cycle transition has been suggested by recent studies in murine models. To investigate the clinical relevance of these laboratory studies, a group of 116 paraffin-embedded non-Hodgkin's lymphoma (NHL) biopsy specimens (Working Formulation Groups D-H, and J) from a cooperative group study of cellular DNA content were analyzed for the 14;18 translocation using polymerase chain reaction (PCR)-based methods and, if sufficient tissue remained, for BCL-2 and BAXexpression by immunohistochemistry. The results of these studies were then compared with the results of the previously performed flow cytometric analysis of ploidy and proliferative activity (S-phase-fraction). BCL-2 expression was inversely associated with proliferative activity (P = .001; n = 41), but there was no association between staining for Bax and %S-phase. Ploidy was not associated with either BCL-2 or BAX expression. The t(14;18) was detected in 21 of the 54 cases in which PCR-amplifiable DNA was recovered; 20 of these occurred at the major breakpoint region and 1 at the minor breakpoint region. High levels of BCL-2 orBAX expression occurred independently of t(14;18). There was no association between t(14;18) and either ploidy or proliferative activity. The inverse relationship between BCL-2 expression and proliferative activity in the intermediate- and high-grade NHLs is consistent with recent studies suggesting that Bcl-2 both retards entry into the cell cycle and inhibits apoptosis.