ALBERT

Description: Programmed Death Ligand 1 (PD-L1) is expressed on antigen presenting cells and serves to inhibit activation of T cells through its receptor, Programmed Death 1 (PD-1). PD-L1 is aberrantly expressed on epithelial malignancies and may prevent an effective host antitumor immune response. However, the pattern of expression and function of PD-L1 in non-Hodgkin lymphoma (NHL) is largely unknown. We examined 77 primary NHL tissue specimens and 16 NHL cell lines for expression of PD-L1. PD-L1 was detected by immunohistochemical staining in all 14 anaplastic large cell lymphoma (ALCL) specimens (both ALK+ and ALK-), and in 18 of 22 diffuse large B cell lymphomas (DLBCL). PD-L1 was expressed in all cases of Hodgkin’s, mediastinal B cell, and grey zone lymphoma, 50% of peripheral T cell lymphomas, 15% of follicular lymphomas, and 33% of mantle cell lymphomas. Among DLBCL cases subtyped into germinal-center B (GCB) and non-GCB using CD10, BCL-6, and MUM-1 (Hans et al, Blood2004;103:275), 8 of 12 (66%) GCB cases expressed PD-L1, compared to 10 of 11 (91%) of non-GCB cases (p=0.31). Among NHL cell lines, all 9 B cell lines were negative for PD-L1, as measured by flow cytometry, but all 5 ALCL cell lines were strongly positive. Therefore, we chose to focus on ALCL to study the role of PD-L1 in modulating anti-lymphoma T cell activity. PD-L1 expressed by ALCL was biologically active in that proliferation of allogeneic T cells co-cultured with Karpas 299 ALCL cells was significantly enhanced by blocking PD-L1 with monoclonal antibodies. To further study tumor-T cell interactions, malignant ascites from a patient with newly diagnosed ALK+ ALCL, containing approximately equivalent proportions of PD-L1-expressing tumor cells and tumor-associated T cells, was used as an autologous system. Secretion of interferon-γ after 3- or 5-day incubation of the T cell/tumor mixture with phytohemagglutinin (a polyclonal T cell activator) was increased four-fold in the presence of anti-PD-L1 antibody, as compared with control antibody or media alone. Secretion of other inflammatory cytokines, including IL-1, TNFα, IL-5, IL-13, and MIP1α, was also markedly increased with the addition of anti-PD-L1 antibody to the mixture of tumor cells and lymphocytes. In conclusion, PD-L1 is expressed in a broad array of non-Hodgkin lymphomas, particularly in ALCL. Blockade of tumor-associated PD-L1 promoted activation of adjacent T cells. PD-L1 may play a role in thwarting an effective antitumor immune response, and thus represents an attractive target for lymphoma immunotherapy using anti-PD-L1 or anti-PD-1 monoclonal antibodies. Heterogeneity of PD-L1 expression among DLBCLs may be related to GCB subtype or other biological properties, and these associations are being explored in a larger set of DLBCL cases. Table 1. PD-L1 expression by lymphoma subtype. Subtype Number PD-L1+ % Anaplastic large cell lymphoma 14 14 100% Diffuse large B cell lymphoma 22 18 82% T cell rich DLBCL 7 4 57% Follicular lymphoma 13 2 15% Mantle cell lymphoma 6 2 33% Mediastinal DLBCL 2 2 100% Hodgkin lymphoma 5 5 100% Grey zone lymphoma 1 1 100% Peripheral T cell lymphoma 7 4 57%

Description: Interleukin-21 (IL-21) is a member of the common gamma chain cytokine family, which includes IL-2, IL-7 and IL-15, and serves to activate NK cells and CD8+ T cells, as well as modulate B cell functions. Like IL-2, IL-21 can enhance antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, unlike IL-2, IL-21 can render effector T cells resistant to suppression by T reg cells, and can have direct anti-tumor effects against malignant B cells. IL-21 has been shown to promote apoptosis in follicular lymphoma cells, and to induce granzyme B expression in chronic lymphocytic leukemia cells and sensitize them to apoptosis. In a human lymphoma xenograft model, combination treatment with rituximab plus recombinant IL-21 (rIL-21) led to increased survival compared to either agent alone. To further evaluate the potential safety, pharmacokinetics, and anti-tumor effects of combining rIL-21 with rituximab, a phase 1, two-part dose-escalation study was initiated in patients with relapsed CD20+ B cell lymphomas. For dose escalation, cohorts of 3 patients each received weekly rituximab (375 mg/m2) on days -7, 0, 7, 14, and 21, and rIL-21 at 1 of 3 dose levels (30, 100, or 150 g/kg) on days 0, 7, 14, and 21. Patients without disease progression at day 36 were eligible to receive a second cycle beginning 2 weeks later, and CT scan assessments were repeated at day 50 of cycle 2. Enrollment to an expansion cohort of up to 12 additional patients for treatment at the maximum tolerated dose was initiated. A total of 15 patients have been enrolled to date, including 9 dose-escalation patients, all of whom are evaluable for clinical response. The latter include 4 with follicular lymphoma, 4 with small lymphocytic leukemia (SLL), and 1 with marginal zone lymphoma. The median number of prior regimens was 3 (range 1–8), with 8/9 patients having had prior rituximab (1–3 cycles). No patient receiving 100 g/kg or higher of rIL-21 had disease progression, and 7 of 9 patients completed 2 treatment cycles. Overall best responses included 2 CR, 3 PR (including 2 patients whose last response to rituximab lasted 〈 6 months), and 3 SD by Cheson criteria, for an overall response rate of 56%. No dose limiting toxicities occurred in the first cycle at any dose. Most adverse events were grade 1–2 and included flu-like symptoms, fatigue, pruritus, insomnia, and diarrhea. Laboratory abnormalities were generally mild to moderate and included lymphopenia, transaminase elevations, thrombocytopenia in one patient and hypophosphatemia. Retreatment at 150 g/kg was associated with transient grade 3 nausea, vomiting, and diarrhea in one patient, while a second patient had grade 2 lower extremity edema. Thus, the 100 g/kg dose was chosen for cohort expansion. Combination treatment with interleukin-21 plus rituximab for up to two 4-week cycles is generally well-tolerated and associated with clinical responses, even in subjects heavily pre-treated with rituximab. Enrollment in the 100 g/kg expansion cohort is ongoing. These encouraging results support further evaluation of this combination in phase 2 trials.

Description: Introduction Ibrutinib, a Bruton's tyrosine kinase inhibitor, was approved in the U.S. for the treatment of relapsed or refractory mantle cell lymphoma (MCL) in November of 2013. However, real-world data on ibrutinib use for the treatment of MCL is limited. The purpose of this study was to examine ibrutinib use, dosages, and reasons for treatment discontinuation among MCL patients treated in a community oncology practice setting. Methods The study population consisted of adult (≥18 year old) MCL patients treated with ibrutinib between November 1, 2013 and October 31, 2016, who were not enrolled in a clinical trial and had at least 2 visits to a US Oncology Network (USON) clinic. Patients with other primary cancers were excluded. Patient data were sourced from the USON's electronic health records system, iKnowMed (iKM)™. The structured iKM database provided information on demographics and clinical and treatment characteristics. Manual chart review was used to confirm ibrutinib treatment patterns. Duration of ibrutinib therapy (DOT), overall survival (OS), and progression-free survival (PFS) from systemic treatment initiation were estimated using Kaplan-Meier methods. Events were defined as death in the OS analysis, and progression or death in the PFS analysis. Patients were censored if their treatment was ongoing for DOT. Censors for OS and PFS were patients lost to follow up or those who did not experience a failure event within the study period. Results 159 eligible MCL patients were identified through iKM. The majority of patients were Caucasian (n=141, 88.7%), male (n=121, 76.1%), and diagnosed with Stage IV disease (n=117, 73.6%). Median follow-up for the population was 16.1 months. Approximately 7.5% (n=12) of patients received ibrutinib as first-line therapy (1L), compared to 54.1% (n=86) in 2L and 38.4% (n=61) in 3L or beyond. Median ibrutinib dose at initiation was 560mg (range: 140-700). During ibrutinib treatment, 16.4% (n=26) of patients experienced a dose reduction. Dose holds occurred in 30.2% (n=48), 66.7% (n=32) due toxicities. The overall discontinuation rate was 83.6% The primary reason for discontinuation was disease progression (n=46, 34.6%) followed by toxicities (n=34, 25.6%). Median DOT was higher for patients initiating treatment in 3L+ (14.9: 95% CI 8.8-17.1) compared to other lines. Median PFS was 19.6 (95% CI: 16.5-24.3) for the overall population and median OS was 25.8 months (95% CI: 19.9-not reached). Conclusions Our real-world findings on survival are consistent with those from clinical trials on ibrutinib in relapsed/refractory MCL, although our observed discontinuation rate (~84%) was higher than that of the trial (~58%), which had a similar median follow-up time (16.1 months vs. 15.3 months, respectively). Our findings provide additional data on MCL treatment patterns and patient outcomes in clinical practice. Disclosures Sharman: Acerta: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Kabadi:AstraZeneca: Employment. Clark:McKesson Specialty Health: Employment, Equity Ownership. Amirian:McKesson Specialty Health: Employment. Andorsky:Celgene: Research Funding; CTI BioPharma: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy.

Description: Introduction: There are limited treatment options for patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who are not candidates for high-dose therapy and stem-cell transplant (SCT). Reasons for ineligibility for intensive treatment include advanced age and overall condition, comorbidities, failure to respond to standard salvage treatment regimens, progressive disease following previous SCT, and presence of other adverse risk factors. The PIX306 study evaluated the efficacy of pixantrone + rituximab (PIX+R) compared with gemcitabine + rituximab (GEM+R) in patients with relapsed aggressive B-cell NHL in this particular clinical setting. We present the primary results of the core analysis of the PIX306 trial. Methods: PIX306 was a phase 3, multicentre, open-label, randomized trial in patients aged ≥18 years diagnosed with de novo diffuse large B-cell lymphoma (DLBCL), DLBCL transformed from indolent lymphoma, or grade 3 follicular lymphoma (FL) who relapsed after at least one standard rituximab-containing multi-agent regimen. Primary refractory de novo DLBCL and grade 3 FL, defined as progression within 12 weeks of the last cycle of the first-line treatment regimen, was an exclusion criterion. Patients were randomly allocated 1:1 to receive PIX 50 mg/m2 or GEM 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, each in combination with R 375 mg/m2 on day 1, for up to 6 cycles, with follow-up for progression up to 96 weeks. The primary endpoint was progression-free survival (PFS) as determined by the Independent Radiology Committee (IRC). Disease response was assessed according to the Modified IWG 2007 Revised Response Criteria. The current analysis is based on 197 PFS events (IRC). Overall survival (OS), complete response (CR), overall response rate (ORR), and safety were secondary endpoints. Results: The ITT population included 312 patients; 155 and 157 patients were randomly allocated to receive PIX+R and GEM+R, respectively. Groups were well balanced; no statistically significant differences in baseline demographics were shown (Table). Median age was 73 years (range: 26-91 years). Overall, 193 (61.9%) patients had received only one line of prior chemotherapy. Most patients (n=242; 77.6%) had de novo DLBCL, 43 (13.8%) had DLBCL transformed from indolent NHL and 27 (8.7%) had grade 3 FL. The majority of patients had Ann Arbor stage III/IV (n=230; 73.7%) disease, 166 (53.2%) patients had an IPI score of ≥3, and in 195 (62.5%) patients extranodal disease was diagnosed at baseline. In total, 116 (37.2%) patients had their first disease relapse within 1 year following the initiation of the front-line therapy for DLBCL or FL. Thirty-three (10.6%) patients had undergone a previous SCT. The study did not meet its primary objective of efficacy, as measured by PFS, of PIX+R vs GEM+R [P= 0.28; HR=0.85 (95% CI: 0.64, 1.14)]. The median PFS (95% CI) in the PIX+R and the GEM+R groups were 7.3 months (5.2; 8.4) and 6.3 months (4.4; 8.1), respectively. Median OS was 13.3 vs 19.6 months [HR=1.13 (95% CI: 0.83, 1.53), P=0.43], CR was observed in 35.5% vs 21.7% of patients, and ORR was 61.9% vs 43.9% in the PIX-R and GEM-R groups, respectively. Both regimens were reasonably tolerated and no new safety signals were reported. Cardiac failure was reported as a serious adverse event in 3 and 2 patients (2.0% and 1.3%) receiving PIX-R and GEM-R, respectively. Conclusions: This is the first study to investigate the efficacy of PIX+R vs GEM+R as second-line or later therapy in patients with relapsed aggressive B-cell NHL who are not eligible for SCT and who have few therapeutic options. Even though the present study did not meet its primary endpoint, the PFS observed in both the PIX+R and GEM+R groups were longer than the study outcomes previously reported in similar patient populations. Disclosures Salles: Merck: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Acerta: Honoraria; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Morphosys: Honoraria. Jurczak:Epizyme: Research Funding; Celgene: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Afimed: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Acerta: Consultancy, Research Funding; AstraZeneca: Consultancy; European Medicines Agency: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; TG therapeutics: Research Funding. Andorsky:AstraZeneca: Consultancy; CTI BioPharma: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy. Quick:CTI BioPharma: Research Funding. Singer:CTI BioPharma: Employment, Other: Stock options. Bedi Singh:CTI BioPharma: Employment, Other: Stock options. Wang:CTI BioPharma: Employment, Equity Ownership. Egorov:Servier: Employment. Gabarroca:Servier: Employment. Pettengell:CTI: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Servier: Honoraria; Takeda: Honoraria.

Description: Introduction:The prognosis is poor for patients with follicular lymphoma (FL) who experience early relapse within 2 years of initial diagnosis and for those who are double refractory to both rituximab and chemotherapy (Casulo et al. J Clin Oncol 2015). Avadomide, a cereblon-modulating agent that promotes degradation of the hematopoietic transcription factors Aiolos and Ikaros, is being examined in this setting. Avadomide demonstrated promising clinical activity in combination with obinutuzumab or rituximab in relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and FL (Michot et al. Blood 2017; Ribrag et al. Blood 2017). Herein, we report FL subgroup analyses for the avadomide plus rituximab combination (Arm D) of the CC-122 DLBCL-001 study in both lenalidomide-naïve and treated patients. Methods: CC-122-DLBCL-001 (NCT02031419) is aphase Ib dose escalation/expansion study of avadomide, CC-223, and CC-292 given orally as doublets, and as triplets in combination with rituximab, as well as avadomide plus rituximab doublets, in patients with R/R DLBCL or FL after ≥1 prior line of therapy. In the dose expansion phase of the study, patients received avadomide once daily (QD) for 5 days/week (5/7 d), with a fixed dose of intravenous rituximab 375 mg/m2/cycle (28-day cycle). The study endpoints were safety, tolerability, pharmacokinetics, preliminary efficacy (overall response rate [ORR] and complete response [CR]), and blood pharmacodynamic markers of avadomide. Results: As of May 1, 2018, 37 patients with FL were enrolled in the Arm D expansion group, including 29 in cohort 1 (no prior lenalidomide) and 8 in cohort 2 (≥2 cycles of prior lenalidomide). Baseline patient characteristics were similar between the two cohorts. In the total FL population, the median age was 61 years (range, 41-81 years), 54% were male, and 46% had an Eastern Cooperative Oncology Group performance status of 1. The median number of prior systemic anticancer regimens was 3 (range, 1-8). At disease diagnosis, three patients (8%) had bulky disease (≥7 cm in single dimension) and 7 (19%) had high Follicular Lymphoma International Prognostic Index scores. Twenty-three patients (62%) were refractory to rituximab and 11 (30%) were double-refractory to rituximab and an alkylating agent. As of the data cutoff, 27 patients (71%) were ongoing and no evaluable patients had experienced a dose-limiting toxicity. The most common (≥10%) any-grade adverse events (AEs) were neutropenia (46%) and anemia (24%). Grade 3/4 AEs occurring in 〉1 patient were neutropenia (32%); fatigue, dizziness, and anemia (8% each); febrile neutropenia and diarrhea (5% each). Six patients (16%) experienced serious AEs related to study drugs. One patient died during the study (sepsis considered possibly related to study treatment). Avadomide dose reduction occurred in 7 (19%) patients. Among all FL patients, the ORR was 65% with 8 patients (22%) achieving a CR. Response rates appeared to be independent of prior lenalidomide treatment, with an ORR of 62% (CR=14%) in cohort 1 and an ORR of 75% (CR=50%) in cohort 2. The median follow up for progression-free survival (PFS) was 6.3 months and 49% of patients had

Description: Background:Lenalidomide is an immunomodulatory agent with direct and immune-mediated mechanisms of action, as well as clinical activity in NHL. Recent studies in frontline and relapsed/refractory NHL show high activity for lenalidomide plus rituximab (R2), supporting further study of this combination. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, open-label study of subjects with grades 1-3b FL (including transformed lymphoma [TL]), MZL, or MCL who received 〉=1 prior therapy and had stage I-IV, measurable disease (〉1.5 cm). Subjects received 12 cycles of R2 induction, consisting of oral lenalidomide 20 mg/day, days 1-21 per 28-day cycle (d1-21/28) plus intravenous rituximab 375 mg/m2, days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 3, 5, 7, 9, and 11 (28-day cycles). Subjects with stable disease (SD) or better after induction were then were randomized 1:1 to R2 vs. rituximab maintenance. Stratification to the 2 maintenance arms was based on histology (FL grade 1-3b and TL vs. MZL vs. MCL), number of prior lines of antilymphoma therapy (2), and age (=65 years).Maintenance R2 consisted of lenalidomide 10 mg/day, d1-21/28, cycles 13-30 plus rituximab 375 mg/m2, day 1 of cycles 13, 15, 17, 19, 21, 23, 25, 27, and 29 (Arm A). Rituximab maintenance alone was on the same schedule (Arm B). Subjects receiving R2 maintenance after 18 cycles are eligible to continue maintenance lenalidomide monotherapy 10 mg/day, d1-21/28 (optional per subject and/or investigator discretion) until disease progression as tolerated. The primary endpoint isprogression-free survival (PFS) comparing maintenance arms using a two-sided test with alpha=0.05 and HR=0.67. Secondary endpoints include safety, overall survival, and response rates. Efficacy is evaluated per modified 1999 IWG criteria and safety per NCI CTCAE version 4.03. Results: As of Jan 11, 2016, 135 subjects have been enrolled, including 91 (67%) with FL, 24 (18%) with MZL, 19 (14%) with MCL, and 1 (1%) with TL. At the time of enrollment, subjects had a median age of 66 years (range, 41-91); 81% had stage III/IV disease. Subjects had received a median of 2 prior therapies (range, 1-10), with 36% refractory to rituximab (defined as SD/PD to or PR/CR for

Description: Reported predictors of quality of life (QOL) after stem cell transplantation (SCT) are largely limited to biological variables. We used data from a large prospective study of autologous and allogeneic SCT recipients to test whether self-reported functioning also predicts later QOL. Surveys were collected at baseline and at 6 and 12 months following transplant and included sociodemographic variables, self-reported physical and mental functioning, and perceptions of health and recovery. Multivariate models for QOL variables at 6 and 12 months were constructed, considering baseline clinical variables (age, sex, type of transplant, disease status) and baseline QOL variables (the Short-Form 36 (SF36) physical (PCS) and mental health (MCS) scales, and a rating scale (RS)), controlling for clinical events (acute and chronic graft-vs.-host (GVHD), and relapse). Variables with p