Advani, Ranjana H.

Abstract Abstract 1618 Introduction: Primary breast lymphoma is a rare type of non-Hodgkin lymphoma (NHL), representing about 1% of breast tumors and 2% of extranodal NHL. Diffuse large B-cell lymphoma (DLBCL) is the most common primary subtype presenting in the breast. Due to the low incidence of primary breast DLBCL, outcome data is limited. The aim of this study was to retrospectively assess the natural history of primary breast DLBCL in the pre and post rituximab eras, with specific emphasis on the incidence of local, systemic and central nervous system (CNS) relapses. Methods: Data was retrospectively collected on patients with primary breast DLBCL from seven USA academic medical centers. Institutional review board approval was obtained at each participating site. Patients were identified through institutional databases and tumor registries at each site. Charts were reviewed to obtain demographic and clinical variables including treatment history and dates of relapse and death when applicable. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. All histologies apart from primary DLBCL were excluded. Overall survival (OS) was calculated from the diagnosis date to the date of death or last follow-up. Time to Progression (TTP) was calculated from diagnosis data until the date of pathological evidence of recurrence or death. Data were summarized using descriptive statistics, and survival was analyzed using the Kaplan-Meier method. Results: Between 1984 and 2012, 75 patients were identified who met the eligibility criteria. The median age was 62 years (range 17–87); 81% presented with a palpable mass; 12% had their disease detected incidentally by mammography; 4% presented with B-symptoms; 59% had right breast involvement; 67% had stage I and 33% had stage II disease. The stage-adjusted international prognostic index (IPI) score was 0 in 28% of patients, 1 in 41%, 2, in 25%, 3 in 4% and 4 in 1%. 91% of patients were treated with chemotherapy; 31% of these were treated in the pre-rituximab era and 69% received rituximab. Radiation therapy (RT) was utilized in 68% of patients and was the only treatment modality in 8% of those receiving RT. 8% of patients received CNS prophylaxis with intrathecal chemotherapy. After a median follow-up of 4.5 years (range 0.6 – 20.6 years), the Kaplan-Meier estimated median TTP was 10.4 years (95% CI 6.2 – 14.6 years) and the median OS was 14.6 years (95% CI 6.5 – 22.6 years). The 5-year TTP and 5-year OS were 65% (95% CI 53–77%) and 75% (95% CI 64–86%) respectively. Among the patients who relapsed, 67% occurred within the first 2 years. A total of 7 relapses in the breast were observed, none in patients treated with combination of chemotherapy and RT. In univariate analysis, rituximab exposure was not associated with any difference in TTP or OS. The stage-adjusted IPI was associated with OS; the 5-year OS was 88% (95% CI 79–98%) in patients with a score of 0–1 versus 48% (95% CI 25–71%) in those with a score of 2–4 (log rank p < 0.001). The very limited-disease group with a stage-adjusted IPI of 0 had a 5-year OS of 94% (95% CI 83–100%) compared to all others who had a 5-year OS of 67% (95% CI 52–81%; log rank p = 0.001). There was no difference in TTP and OS in patients with solitary versus multiple breast masses or between patients with tumors less than versus more than 7cm. Patients receiving RT in addition to chemotherapy had a longer TTP than those who did not (log rank p = 0.03), but RT was not associated with an improved OS. Patients who relapsed and underwent stem cell transplant (SCT) had similar OS to those who never relapsed. Ten patients (13%) had CNS relapse (3 with leptomeningeal disease, 5 with brain parenchymal disease and 2 with both). All CNS relapses occurred within the first 2.8 years from the time of diagnosis. There was no difference in the rate of CNS relapse in the patients who received IT prophylaxis versus those who did not. Conclusions: In this multicenter study, the largest published to date, primary breast DLBCL appears to have a worse prognosis than early-stage DLBCL in nodal or other extranodal sites. RT was associated with improved TTP. Patients who relapsed were successfully salvaged with SCT, and had similar survival times to those who never relapsed. A high CNS relapse rate (∼1 in 8 patients, including parenchymal disease in 70%) was observed. The small numbers preclude definitive conclusions on the value of intrathecal prophylaxis or the utility of rituximab. Disclosures: No relevant conflicts of interest to declare.

Abstract Background The international prognostic score (IPS) (Hasenclever et al., NEJM 1988) uses 7 factors (age> 45, male sex, hemoglobin<10.5, stage IV, leukocytosis > 15,000, and lymphopenia< 600) to predict a 5 year freedom from progression (FFP) of 42%-84% and overall survival (OS) of 56%-89% for patients with advanced HL. Constructed from a retrospective analysis of patients treated before 1992, the IPS continues to be the most commonly used risk stratification index for advanced HL. Recent studies suggest that the predictive range of the IPS has narrowed due to improved outcomes of patients treated with current therapy (Moccia et al. JCO 2012). In this report we prospectively evaluated the ability of the individual components of the IPS to predict outcome in patients enrolled on the US Intergroup trial E2496. Methods All seven IPS (IPS-7) variables were recorded for all patients at study entry. FFP was defined as the time from study entry to disease progression or relapse; deaths that occurred during remission that were not preceded by disease progression/relapse were censored. OS was defined as the time from study entry to death from any cause. Kaplan-Meier methodology was used to construct survival curves. Univariate and multivariate analysis (MVA) was performed using Cox proportional-hazards models. We subsequently constructed an alternative prognostic score utilizing the factors which were significant on MVA (PS-3). Results From 1996-2006, 854 patients with advanced HL, were randomized to treatment with either ABVD or Stanford V, with no significant differences in outcome (Gordon et al, JCO 2013). While the IPS-7 remained prognostic it did not stratify the lowest risk patients (0-1 risk factor) or patients with 3-5 risk factors, as its predictive range was narrowed due to improved clinical outcomes (Fig 1a and 2a). Table 1 shows the univariate and multivariate analysis for IPS-7 and outcomes. In contrast to the original IPS-7, on MVA, only two factors, hemoglobin and stage were significant for FFP, and three factors for OS: hemoglobin, stage, and age. We then evaluated a new 3 factor score (PS-3) utilizing variables significant on the MVA. The PS-3 was significant for both FFP (p=0.0001) and OS (p<.0001) and clearly separated patients into 4 distinct risk groups with either: 0, 1, 2 or 3 risk factors. The five year FFP was 83%, 74%, 68%, and 63% and OS was 95%, 85%, 75%, and 52% for patients with 0, 1, 2, and 3 risk factors, respectively (Table 2, Fig 1b and 2b). Conclusion In E2496, for patients with advanced HL, the PS-3 may stratify patients more clearly compared to IPS-7 and provide a simpler model to assess risk. Studies comparing PS-3 with IPS-7, and are ongoing. The incorporation of novel biomarkers and biologic factors into PS-3, as well as validation with other data sets is warranted. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Outcomes for patients with DLBCL have improved over the past decade, with the addition of rituximab to CHOP or CHOP-like multi-agent chemotherapy regimens improving the 3-year overall survival (OS) of patients by 10-16% compared to multi-agent chemotherapy alone (Coiffier 2002; Pfreundschuh 2010). However, patients with high-intermediate or high-risk disease have relatively poor outcomes with the standard RCHOP regimen (Ziepert 2010); in a recent prospective trial of intermediate- and high-risk DLBCL patients, complete response (CR) rate for RCHOP alone was 26% (Hainsworth 2011). Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising the antibody cAC10, specific for human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Brentuximab vedotin has demonstrated compelling activity as a single agent in patients with relapsed or refractory DLBCL, even those with low CD30 expression (Bartlett 2013). This phase 2, randomized, open label study is designed to evaluate the antitumor activity and safety of brentuximab vedotin (1.2 or 1.8 mg/kg) when administered in combination with standard RCHOP chemotherapy (A+RCHOP) for the front-line treatment of patients with CD30-unselected high-intermediate/high-risk (standard IPI score 3–5 or age-adjusted IPI [aaIPI] score 2–3) DLBCL (ClinicalTrials.gov NCT01925612). Methods Patients were randomized to receive up to 6 cycles of either 1.2 or 1.8 mg/kg brentuximab vedotin administered IV on Day 1 of every 21-day cycle in combination with RCHOP; prednisone was administered orally on Days 1-5 of every 21-day cycle. Assessments included disease response per Cheson 2007, as evaluated by the investigator, surveillance of adverse events (AEs), physical examination findings, and laboratory testing. The primary endpoints for this study are the CR rate at the end of treatment (EOT) and the type, incidence, and severity of AEs. Key secondary endpoints include objective response rate (ORR), progression-free survival (PFS), and OS. Results At the time of the planned interim analysis, 33 patients were enrolled (17 patients, 1.2 mg/kg A+RCHOP; 16 patients, 1.8 mg/kg A+RCHOP). Median age for all patients was 66 years (range, 21 to 81). At baseline, 36% were high-risk (IPI 4-5, aaIPI 3) and 64% were high-intermediate risk (IPI 3, aaIPI 2). The majority of patients (73%) had Stage IV disease and 33% had an ECOG status of 2. At the time of interim analysis, a total of 12 patients (6 patients in each arm) had completed EOT. Across both dose levels, ORR was 92% (11/12), with 7 CRs (58%), 4 PRs (33%), and 1 PD. The patient with PD subsequently died. Patients with PR had a median reduction of baseline tumor size of 84% (range, 92% to 83%), as measured by SPD. The only patient with follow-up after EOT converted from PR to CR without subsequent therapy. Treatment-emergent AEs occurring in ≥30% of patients treated (26/33) were nausea, diarrhea, peripheral sensory neuropathy, fatigue, and decreased appetite. Grade 3 or higher events occurring in more than 2 patients were febrile neutropenia and neutropenia. Events of peripheral neuropathy occurred equally per arm (46%, 1.2 mg/kg A+RCHOP; 46% 1.8 mg/kg A+RCHOP) and were generally Grade 1 or 2 (15% and 23%, respectively); events were of similar grade across dose levels. The median time to onset of any grade of peripheral neuropathy was 6 weeks (range, 2 to 10 weeks). Five patients (19%) had dose reductions due to peripheral neuropathy and 3 patients (12%) had dose reductions due to febrile neutropenia. One patient who received 1.2 mg/kg A+RCHOP discontinued study drug due to an AE (thrombocytopenia). Conclusions At doses of 1.2 or 1.8 mg/kg, A+RCHOP exhibited manageable toxicity in the treatment of newly-diagnosed DLBCL; the incidence of peripheral neuropathy was similar to single-agent administration of brentuximab vedotin (Pro 2012, Younes 2012) and RCHOP alone (Rummel 2013, Flinn 2014). In 12 patients with response-assessable, high-intermediate and high-risk DLBCL, A+RCHOP showed encouraging antitumor activity, with an ORR of 92% and a CR rate of 58%. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. . Farber:Seattle Genetics, Inc.: Research Funding. Budde:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Jansseen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Holkova:Seattle Genetics, Inc.: Research Funding. Halwani:Seattle Genetics, Inc.: Research Funding. Knapp:Takeda Pharmaceuticals International Co.: Research Funding; EMD Serono: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Merck: Research Funding; Heron Pharmaceuticals: Research Funding, Travel expenses, Travel expenses Other; Genentech: Research Funding, Travel expenses, Travel expenses Other; Seattle Genetics, Inc.: Research Funding; Pharmacyclics: Research Funding. Fayad:Seattle Genetics, Inc.: Consultancy, Research Funding. Kolibaba:Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Janssen: Research Funding; Astra Zeneca: Research Funding.

Abstract Abstract 1671 Poster Board I-697 Background Bevacizumab (Avastin), a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF-A), is approved in combination with chemotherapy in lung, colorectal, breast and brain cancers. VEGF-A expression is reported in all lymphoma subtypes, with strongest expression in PTCL. Given the relatively poor prognosis of PTCL with standard therapy, we combined bevacizumab (A) with CHOP in the ECOG 2404 phase II trial. Methods Untreated PTCL pts with a normal baseline cardiac ejection fraction received bevacizumab 15 mg/ kg IV and CHOP chemotherapy on day 1 for 6-8 cycles. Patients (pts) with CR/PR/SD received maintenance therapy with bevacizumab 15 mg/ kg IV q 3 weeks for 4 cycles. Due to the reported 3.7% incidence of cardiac toxicity associated with bevacizumab in metastatic breast cancer pt previously exposed to anthracyclines (Avastin package insert), cardiac function was monitored prospectively with ejection fraction (EF) determination at the completion of A-CHOP prior to the start of bevacizumab maintenance. Results Among 33 pts who came off study, toxicity data are available for all and coded using CTCAE Version 3.0. 22 received at least 4 cycles of A-CHOP (median treatment duration 3.6 months (< 1-10.6 months). One or more designated cardiac toxicities were recorded for 5 of these 22 pts. Congestive heart failure (CHF), defined as grade 2-4 left ventricular dysfunction was recorded in 4 pt (18%, 90% CI 5.2%-40.3%): grade 4 (n=1), grade 3 (n=3). In 3 pts clinical CHF occurred after A-CHOP x 6 and in one during bevacizumab maintenance after A-CHOP x 8. The median time to development of a cardiac adverse event was 5 months (3.5 – 8.8 months). One pt required a ventricular assist device in addition to medical management. In 3 of the 4 pts, ongoing medical management for CHF has been required. Other cardiac toxicities included ventricular arrhthymia (one grade 4, one grade 2), and one grade 2 cardiac troponin elevation. In addition, one patient experienced sudden death of uncertain cause. Three pts developed thromboses or embolic toxcities (two grade 4 and one grade 3). Conclusions We observed four cases of clinical CHF early after cumulative doxorubicin doses of 300-400 mg/m2 in our study, The incidence of CHF among study patients who received 4 or more A-CHOP cycles is concerning and suggests that bevacizumab may potentiate the adverse cardiac effects of anthracyclines, resulting in clinically significant toxicity. Careful monitoring of cardiac function is warranted in ongoing trials combining bevacizumab and doxorubicin in lymphomas and solid tumors to assess long-term safety and better understand underlying mechanisms and risks. Disclosures No relevant conflicts of interest to declare.

Abstract 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.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin’s lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

Background:Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post‐translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors.Aims:Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T‐cell lymphoma (AITL) and CXCL12+ peripheral T‐cell lymphoma (PTCL) patients (pts).Methods:This Phase 2 study (NCT02464228) is a multi‐institutional, single‐arm, open‐label trial initially designed as a two‐stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age >/ = 18 years and a performance status of 0–2. Based on initial findings, the study was amended to include a cohort of AITL (n = 12) and PTCL (n = 12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1–21 of 28‐day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in pts who received tipifarnib and standard of care treatment.Results:As of 20 February 2019, 43 PTCL pts (20 AITL, 21 PTCL‐NOS, 1 ALK‐ ALCL, 1 gamma‐delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 24 pts in the ongoing AITL histology and CXCL12 cohort. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts had at least one treatment‐emergent adverse event (TEAE); 39 (90%) had at least 1 study drug‐related TEAE and 12 (28%) at least 1 drug related SAE. The most frequently observed drug‐related TEAEs of Grade ≥3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (44%), thrombocytopenia (37%), leukopenia (28%), anemia (21%) and febrile neutropenia (21%). There have been 14 deaths on study; none were related to study drug. Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable pts), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the CXCL12+ cohort (n = 3 evaluable pts), 1 PR and 2 SD have been observed, with 4 pts pending cycle 2 response evaluation. CXCL12 expression correlated with favorable outcome to tipifarnib treatment. Pre‐treatment high CXCL12 expression had 90% sensitivity and 93% specificity to identify pts who experienced CR/PR/SD on study in a preliminary analysis of 24 pts. The prognosis of CXCL12 was also retrospectively investigated in 73 pts who received standard of care therapy (AITL N = 50, PTCL NOS = 23). A trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR = 1.8, p = 0.09) was observed using the high CXCL12 subset using the cut‐off point that predicted clinical benefit under tipifarnib therapy. Fifty percent of AITL and 35% of non‐AITL samples overexpressed CXCL12.Summary/Conclusion:Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment in the CXCL12+ cohort continues.