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BACKGROUND Pegylated liposomal doxorubicin (PEG-LD) and gemcitabine have single-agent activity in breast and ovarian carcinoma patients. We conducted a Phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in patients with advanced malignancies. METHODS Twenty-six patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of PEG-LD 20 mg/m2 and gemcitabine 1000 mg/m2 administered on Days 1 and 15 of a 28-day cycle. RESULTS The MTD was PEG-LD 20 mg/m2 and gemcitabine 2000 mg/m2 administered on Days 1 and 15 of a 28-day cycle. Dose-limiting toxicity, a Grade 3 rash, was observed in one patient during Cycle 1 and Grade 3 stomatitis and a rash were observed in a second patient during Cycle 2 after administration of PEG-LD 25 mg/m2 and gemcitabine 2000 mg/m2. Other side effects included palmar–plantar erythrodysesthesia, nausea, and fatigue. One complete and two partial responses were observed. CONCLUSIONS The recommended Phase II dose is PEG-LD 20 mg/m2 with gemcitabine 2000 mg/m2 on Days 1 and 15 of a 28-day cycle. A trial with this combination is currently ongoing at this institution comprising patients with refractory ovarian carcinoma. Cancer 2002;95:2223–29. © 2002 American Cancer Society. DOI 10.1002/cncr.10937

Introduction: Outcomes for pts with refractory aggressive NHL are poor with current therapies (Crump, ASCO 2016). Results from the interim analysis of (n=62) of ZUMA-1, the 1st multicenter trial of an anti-CD19 chimeric antigen receptor (CAR) T cell, axi-cel, in refractory aggressive NHL, showed an objective response rate (ORR) of 79% (complete response [CR] 52%; Blood 2016;128:LBA-6). Here we present results from the primary analysis of ZUMA-1. Methods: Pts received a target dose of 2 × 106 anti-CD19 CAR T cells/kg after lowdose conditioning with cy/flu. Eligible pts (≥18 y) had diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL); an ECOG performance status (PS) 0-1; and refractory disease (progressive or stable disease as best response to last prior therapy, or relapsed ≤12 m of autologous stem cell transplant [ASCT]). The primary endpoint for this analysis was ORR in the combined DLBCL, PMBCL, and TFL population. Key secondary endpoints were duration of response (DOR), overall survival (OS), and frequency of adverse events (AEs). The primary analysis was triggered when 92 pts had at least 6 m of follow-up. Results: As of January 27, 2017, 111 pts from 22 institutions were enrolled; 101 pts (91%) received axi-cel. Median age was 58 y (range, 23-76), 67% male, 85% stage IIIIV, 47% IPI 3-4, 77% refractory to ≥2nd line of therapy, and 21% relapsed ≤12 m of ASCT. Axi-cel was successfully manufactured in 110/111 (99%) pts with an average turnaround time from apheresis to the clinical site of 17 d. With an ORR of 82% (n = 92; P Conclusions: Axi-cel significantly improved ORR in patients with refractory aggressive NHL. The CR rate was 7-fold higher compared to historical controls (Crump, ASCO 2016) and nearly half the patients have an ongoing response. Axi-cel demonstrated significant clinical benefit with a manageable safety profile in pts lacking curative treatment options.[F.L.L. and S.S.N. contributed equally to this study.] Funding source: Kite Pharma and in part by funding from the Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program treatment options. Citation Format: Frederick L. Locke, Sattva S. Neelapu, Nancy L. Bartlett, Lazaros J. Lekakis, David Miklos, Caron A. Jacobson, Ira Braunschweig, Olalekan Oluwole, Tanya Siddiqi, Yi Lin, John Timmerman, Jonathan W. Friedberg, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, Jeff Wiezorek, William Y. Go. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axicel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT019. doi:10.1158/1538-7445.AM2017-CT019

High-throughput sequencing provides insights into cancer pathogenesis. The application of genomics technologies to cancers characterized by rare cell populations is a challenge. DNA extracted from bulk tumor samples is a mixture of malignant and non-malignant cells. This is a problem in cancers defined by rare cell populations because it complicates the task of identifying true somatic mutations. Hodgkin lymphoma (HL) exemplifies this challenge. The pathologic hallmark of HL is Hodgkin-Reed-Sternberg (HRS) cells. HRS cells have a low abundance within an affected lymph node (1-30% of tumor microenvironment). Because HRS cells are rare, a limited number of studies have described characteristic genomic events. These studies have examined HL cell lines, and, recently, a small number of flow-sorted HRS-cells (Reichel et. al. 2015). We hypothesized that recurrent somatic mutations can be identified in HRS cells using bulk HL biopsies and ultra deep exome sequencing. The Illumina HiSeq X,which can generate> 1.6 Tb of sequence data per run, is a applicable tool for the discovery of somatic mutations in HL. Frozen tumor (lymph node)/normal (skin) pairs from 31 patients with HL were examined. Three KAPA libraries were constructed per sample. The libraries were pooled, size selected, and captured using an IDT xGen capture reagent. The pools were sequenced across eight lanes of a HiSeq X. A total of 7.04 x 1012 bases were sequenced across all samples with an average of 1.10 x 1011 bases per sample. The mean depth of coverage achieved across all samples was 783.4x (425.9x - 1091.9x). Given the low abundance of HRS cells we anticipated most somatic sites would have a VAF of 1% -5%. Given the level of coverage we anticipate that most somatic variants will have >5 reads of support. Instrument data were processed using the McDonnell Genome Institute somatic variant calling pipeline that includes 5 SNV callers and 3 indel callers. We used these steps to filter variants: min. 50x coverage, max. 5000x coverage, min. 1% tumor VAF, max. 5%, normal VAF, and min. 5 variant reads in the tumor. Here we report preliminary data on mutations in five pilot samples. The remaining 26 will be presented at the meeting. We confirmed 7 previously identified recurrent mutations in HL (Reichel et al. 2015). Within our pilot data 13 recurrently mutated genes were found. The most interesting of our recurrent genes is TNFAIP3, which was the second most frequently mutated gene in Reichel et al. 2015. These data suggest that ultra deep sequencing of tumor samples containing rare HRS cells can identify recurrent somatic mutations. Thus, ultra deep exome sequencing may be a useful discovery tool for rare tumor populations, and will improve our understanding of HL. Citation Format: Felicia Gomez, Kilannin Krysiak, Cody Ramirez, Nancy Bartlett, Amanda Cashen, Friederike Kreisel, Eric Duncavage, Malachi Griffith, Todd Fehniger, Obi Griffith. Deep exome sequencing reveals recurrent somatic mutations in Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2448. doi:10.1158/1538-7445.AM2017-2448

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma (NHL), is associated with a highly heterogeneous clinical course. The genetic landscape of FL is less understood than other B-cell NHLs such as chronic lymphocytic leukemia and diffuse large B-cell lymphoma. With ongoing clinical trials using therapies targeting B cell receptor signaling (e.g., ibrutinib) in FL, recurrent mutations could impact the interpretation of these trial outcomes and the identification of specific patient subpopulations that have increased or decreased clinical benefit. To identify novel recurrent mutations in FL, we designed a large custom capture lymphoma-related gene panel (WUSM-LP) and queried 113 predominantly treatment-naïve FL samples. To design the WUSM-LP reagent (NimbleGen), we targeted the coding regions of 1716 genes identified in exome sequencing data from a cohort of 24 patients (28 samples) with FL combined with genes recurrently mutated in B-cell non-Hodgkin lymphoma in the literature (Krysiak K et al., Blood, 2016). Previously, we applied the WUSM-LP to the discovery cohort and an additional 81, primarily treatment-naïve, FL samples. Using mutations identified in these 105 individuals, we identified 39 significantly mutated genes (SMGs). These included well-characterized genes in FL (e.g., KMT2D, EZH2, TNFRSF14), and identified novel mutations (BTK, HVCN1, and others) thereby expanding the repertoire of mutations affecting genes in the BCR signaling pathway, SWI/SNF complex and histone family. Including novel BTK mutations, we identified 23 (22%) individuals harboring mutations that likely up-regulate signaling downstream of BTK, potentially affecting response rates to BTK-targeting therapies at the point of FL diagnosis. We also focused on the subset FL patients (N=59) that were sequenced within 1 year of front-line therapy in order to identify clinical associations between recurrent mutations and clinical outcomes, comparing mutation status of SMGs to progression-free survival (PFS) rates. Improved PFS was observed in patients harboring HVCN1 mutations (p Since our initial analysis, we have completed sequencing of an additional 174 FL samples with clinical data available. Confirming our earlier observations with an independent cohort, we observed 9 TNFAIP3 truncating, 18 CARD11 coiled-coil domain, 4 BCL10 truncating and 8 BTK mutations in these samples. These mutations affect 18.4% of FL patients in this cohort, are likely to up-regulate NFkappaB signaling and may impact ibrutinib sensitivity. With the additional power of 8 HVCN1 and 110 CREBBP mutations we have identified, we will evaluate the previously identified associations. The analyses of recurrent mutations and clinical correlations in this combined cohort of nearly 300 FL patients are ongoing and will be presented. Citation Format: Kilannin Krysiak, Cody Ramirez, Felicia Gomez, Christopher A. Miller, Robert S. Fulton, Friederike Kreisel, Amanda F. Cashen, Nancy L. Bartlett, Ana Ruano, Eric D. Hsi, Malachi Griffith, Obi L. Griffith, Todd A. Fehniger. Recurrent mutations and clinical outcomes in patients with follicular lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2444. doi:10.1158/1538-7445.AM2017-2444

3025 Background: Axi-cel is an autologous anti-CD19 CAR T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory/aggressive B-cell non-Hodgkin lymphoma (NHL). In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with 76% objective response rate and 47% complete response (Blood 2016;128:LBA-6). We describe, for the first time, a tumor microenvironment immune gene signature associated with CAR T cell treatment (tx) of NHL pts. Methods: Paired biopsies, pre- and within 3 weeks post-axi-cel tx, were analyzed by digital gene expression followed by a pre-specified bioinformatics algorithm applied to IGES15 and IGES21 genes involved in immune-mediated tumor regression (Immunosign; Galon Immunity 2013). Immunosign profiles expression of a pre-defined set of effector T cell, Th1, chemokine, and cytokine genes. Expression analysis and hierarchical clustering were used to define an axi-cel-related tumor immune gene signature. Wilcoxon signed rank test with multiple test correction by FDR (Benjamini-Yekutieli) was used. Results: Gene expression profile comparisons of pre- and post-axi-cel tx biopsies from 14 pts showed profound changes in gene expression within the tumor environment after infusion. The most upregulated genes post-axi-cel tx were CCL5 (RANTES), CTLA4, and GZMA (log2 fold change > 2, P< 0.05, FDR < 0.050). Immune checkpoints PD-L1 and LAG3 were also upregulated post-axi-cel (log2 fold change > 1.6, P< 0.05, FDR < 0.055). Other genes associated with T cell proliferation, homing, and effector function were also upregulated: IL-15, GZMK, CXC3CL1 (Fractalkine), CD8A, and STAT4 (log2 fold change > 1.6; P< 0.05, FDR < 0.074). Additional baseline tumor characteristics and associative analysis will be presented. Conclusions: We define a mechanistic tumor immune gene signature in NHL pts associated with axi-cel tx. This signature comprises upregulation of T cell activation, effector, chemokine, and immune checkpoint genes. These data will potentially lead to rational optimization of T cell interventions in cancer Clinical trial information: NCT02348216.

7537 Background: Follicular lymphoma (FL) is an incurable malignancy with patients (pts) ultimately relapsing following standard therapies. Active immunotherapy has the potential to induce life-long host anti-tumor immunity and disease control. G100 consists of glucopyranosyl lipid-A (GLA), a TLR-4 agonist in a specific formulation. Preclinically, G100 activates dendritic cells, T cells and NK cells, and triggers systemic anti-tumor immunity. In Merkel Cell carcinoma pts, G100 administered intratumorally (IT) induced tumor inflammation and responses including a CR after G100 alone. This is the first study of G100 IT in pts with NHL. Methods: Previously treated or naïve pts with FL with an injectable tumor site and distal sites of disease were eligible. In Part 1, G100 cohorts of 5 or 10µg were enrolled in a 3+3 design, followed by a large tumor ( > 4cm) cohort at 20µg. Pts received 6-9 doses of G100 IT ~qwk after radiation (RT, 2 Gy x2 doses) to the lesion. A 2nd course of G100 could be given without RT to an additional site. Results: As of 31Dec16, all 9 pts in Part 1 dose escalation (3 pts each at 5, 10, or 20 µg/dose) were evaluable for safety and efficacy. An additional 13 pts at 10µg/dose were included in the safety analysis only. No G100-related DLTs or SAEs were observed at any dose level. Of 22 safety pts, all G100 related AEs were grade 1/2 and none occurred in > 2 pts. Tumor biopsies following G100 demonstrated diffuse infiltration of CD8+ T cells in 5/5 pts and T cell repertoire analyses indicated an increased frequency of clonal tumor infiltrating lymphocytes (TILs). Best responses include: 4 PRs (45%), 3 SDs (33%) and 2 pending (22%). Of the 4 PR pts, tumor regression ranged 58-89% including up to 56% shrinkage of abscopal (distal) sites. Conclusions: G100 IT was safe, well-tolerated, induced CD8+ T cell infiltration and expansion of TIL clones. G100/RT treated and abscopal lesion regressions were observed signifying the induction or boosting of systemic anti-tumor immunity. The induction of immune responses, favorable safety profile and clinical activity indicate that G100 IT is an active agent that warrants further investigation. Part 2 enrollment continues with randomization to G100/RT ± pembrolizumab. Clinical trial information: NCT02501473.

TPS7566 Background: Relapsed DLBCL in the rituximab era portends a poor prognosis with only about 25% of patients achieving long-term disease control following 2ndline therapy and AutoHCT. Patients with the ABC subtype have an inferior prognosis at diagnosis than those with GC and are overrepresented at relapse. In order to improve outcomes in ABC-DLBCL, we designed a study targeting disease pathobiology at the time of AutoHCT. Ibr has a safety profile allowing combination with cytotoxic chemotherapy and has single-agent activity with a 37% response rate in patients with relapsed/refractory ABC-DLBCL. Methods: This is an intergroup, randomized, placebo-controlled phase III study combining Ibr or placebo with high-dose chemotherapy during conditioning with AutoHCT and for 12 months following AutoHCT. Pts with relapsed or refractory DLBCL have tissue submitted centrally for real-time review and subtype assignment by GEP (Frederick Laboratory). Key eligibility criteria include no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no progression on prior Ibr. Pts with chemosensitive ABC-DLBCL are randomized to Ibr 560 mg or placebo with BEAM or CBV chemotherapy until day 0. After engraftment, pts receive Ibr 560 mg daily or placebo for 12 additional cycles. Pts with progressive disease on placebo can cross over to Ibr monotherapy. An initial safety cohort of 6 pts is being enrolled to evaluate the tolerability of Ibr with concurrent BEAM and CBV therapy. The primary endpoint is superior 2-year PFS (Ha/H0: 67% vs 50%). Secondary endpoints include time to count recovery, post-transplant response rates, OS, PFS, and incidence of 2arymalignancies. In correlative studies, we will assess the prognostic and predictive role of pre-transplant FDG-PET in the setting of Ibr or placebo therapy, the role of emergent BCR pathway mutations, double hit genetics, and pharmacogenetic determinants on treatment outcome and toxicities. We expect to accrue 296 patients over 4 years. An Alliance/BMT-CTN study: NCT02443077 Clinical trial information: NCT02443077.

7512 Background: Outcomes in activated B cell subtype diffuse large B cell lymphoma (ABC-DLBCL) and r-NHL are poor (Sehn Blood 2015, Crump ASCO 2016). ZUMA-1 is the first, multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells, axi-cel, in r-NHL. Methods: Dosing and eligibility were per Neelapu ASH 2016. The primary endpoint was objective response rate (ORR); secondary endpoints were duration of response (DOR), overall survival (OS), and safety. Cell of origin (COO) and CD19 status were assessed centrally using Lymphoma Subtyping Test NanoString (Wallden JCO 2015) and a validated immunohistochemistry assay, respectively. Results: As of Jan 27, 2017, 111 patients (pts) were enrolled; the manufacturing success rate was 99% with an average 17-d turnaround time; 101 pts (modified intent-to-treat [mITT] population) received axi-cel. In the mITT population, the ORR was 82% (complete response [CR], 54%). With 8.7 m median follow-up, 44% remain in response and 39% in CR. The median DOR was 8.1 m and not reached (NR) for pts with CR. Median OS was NR. Results for clinical and biologic covariates are listed in the table. In pts who received tocilizumab (n = 43) and/or steroids (n = 27) for cytokine release syndrome (CRS) and/or neurologic events (NE), ORR was 84% and 78%, respectively. Most common grade ≥3 adverse events (AEs) were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), thrombocytopenia (24%), and encephalopathy (21%). Rates of grade ≥3 CRS and NE were 13% and 28%, respectively. There were 3 grade 5 AEs (Neelapu ASH 2016). Conclusions: Axi-cel induced an ORR of 82% in pts with r-NHL, response is ongoing in 44% of pts at 8.7 m. Similar clinical responses were observed in pts with r-ABC-DLBCL. AEs were manageable and the use of tocilizumab/steroids did not appear to impact ORR. Drs Locke and Neelapu contributed equally. Funding source: Kite Pharma and Leukemia & Lymphoma Society Therapy Acceleration Program Clinical trial information: NCT02348216. [Table: see text]

Double-hit lymphomas (DHL) with concurrent MYC and BCL2 rearrangements are rare entities with an aggressive clinical course and low overall survival. They usually develop de novo and frequently show a morphologic and immunophenotypic overlap with Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).1 2 The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue has therefore placed these lymphomas in a provisional category of B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL, awaiting further insight into disease course and prognosis.2 We describe the first case of double-hit lymphoma that revealed morphologic and immunophenotypic features of both DLBCL and precursor B-lymphoblastic lymphoma (B-ALL), further highlighting the dilemma in diagnosis and treatment of DHL because of its broad morphologic and immunophenotypic spectrum. A 43-year-old male came to medical attention because of a cough, sore throat, dysphagia and a 20-pound weight loss. Endoscopy revealed a friable mass involving the right epiglottic fold and extending into the false cord. Histologic sections revealed a varied morphology with areas consistent with DLBCL composed of sheets of large pleomorphic cells with mature chromatin and a single prominent nucleolus and other areas more reminiscent of precursor lymphoblastic lymphoma or BL showing monotonous medium-sized cells with fine chromatin (figure 1A–C). In some areas …

Purpose Front-line treatment of peripheral T-cell lymphomas (PTCL) involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50%. This phase I open-label study evaluated the safety and activity of brentuximab vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30+ PTCL. Patients and Methods Patients received sequential treatment (once every 3 weeks) with brentuximab vedotin 1.8 mg/kg (two cycles) followed by CHOP (six cycles) or brentuximab vedotin 1.8 mg/kg plus CHP (BV+CHP) for six cycles (once every 3 weeks). Responders received single-agent brentuximab vedotin for eight to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end points included objective response rate, complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no prespecified comparisons of the two treatment approaches. Results After sequential treatment, 11 (85%) of 13 patients achieved an objective response (CR rate, 62%; estimated 1-year PFS rate, 77%). Grade 3/4 adverse events occurred in eight (62%) of 13 patients. At the end of combination treatment, all patients (n = 26) achieved an objective response (CR rate, 88%; estimated 1-year PFS rate, 71%). All seven patients without anaplastic large-cell lymphoma achieved CR. Grade 3/4 adverse events (≥ 10%) in the combination-treatment group were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%). Conclusion Brentuximab vedotin, administered sequentially with CHOP or in combination with CHP, had a manageable safety profile and exhibited substantial antitumor activity in newly diagnosed patients with CD30+ PTCL. A randomized phase III trial is under way, comparing BV+CHP with CHOP (clinical trial No. NCT01777152).

Many patients with CD30-positive lymphomas such as Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL) respond favorably to frontline chemotherapy [1,2]. However, approximately...

CALGB designed a phase II trial of lenalidomide+bortezomib for relapsed/refractory mantle cell lymphoma (MCL). Induction therapy was lenalidomide (days 1-14) plus bortezomib (days 1/4/8/11), every 21 days for eight cycles. Complete and partial responders (CR, PR) received maintenance lenalidomide (days 1-14) and bortezomib (days 1/8), every 21 days. Primary endpoint was overall response rate; secondary endpoints were CR rate, progression-free- (PFS), event-free- (EFS), and overall survival (OS). Fifty-three eligible patients, median age 67 years, were accrued. Median number of cycles received was 4 (range, 1-82). Median follow-up is 46 (range, 12-67) months. Best response was CR (n=8, 15%), PR (n=13, 25%). 5/8 CR and 4/13 PR patients received maintenance therapy. Of responders, 6 CR/1 PR patients remain in remission at a median of 3.2 years. Thirty-three (62%) patients have died. One-year PFS, EFS, OS are 40%, 25%, and 68%, respectively. This combination will not be pursued further at this dose/schedule.

Purpose Idiotypes (Ids), the unique portions of tumor immunoglobulins, can serve as targets for passive and active immunotherapies for lymphoma. We performed a multicenter, randomized trial comparing a specific vaccine (MyVax), comprising Id chemically coupled to keyhole limpet hemocyanin (KLH) plus granulocyte macrophage colony-stimulating factor (GM-CSF) to a control immunotherapy with KLH plus GM-CSF. Patients and Methods Patients with previously untreated advanced-stage follicular lymphoma (FL) received eight cycles of chemotherapy with cyclophosphamide, vincristine, and prednisone. Those achieving sustained partial or complete remission (n = 287 [44%]) were randomly assigned at a ratio of 2:1 to receive one injection per month for 7 months of MyVax or control immunotherapy. Anti-Id antibody responses (humoral immune responses [IRs]) were measured before each immunization. The primary end point was progression-free survival (PFS). Secondary end points included IR and time to subsequent antilymphoma therapy. Results At a median follow-up of 58 months, no significant difference was observed in either PFS or time to next therapy between the two arms. In the MyVax group (n = 195), anti-Id IRs were observed in 41% of patients, with a median PFS of 40 months, significantly exceeding the median PFS observed in patients without such Id-induced IRs and in those receiving control immunotherapy. Conclusion This trial failed to demonstrate clinical benefit of specific immunotherapy. The subset of vaccinated patients mounting specific anti-Id responses had superior outcomes. Whether this reflects a therapeutic benefit or is a marker for more favorable underlying prognosis requires further study.

Purpose Universal expression of CD20 by malignant cells in nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) led us to evaluate rituximab (R) as a therapeutic option. Patient and Methods Patients with previously treated or newly diagnosed NLPHL were treated with R (375 mg/m2 once per week for 4 weeks) or, after a protocol amendment, with R plus R maintenance (MR; administered once every 6 months for 2 years). Primary and secondary outcome measures were progression-free survival (PFS) and overall response rate (ORR), respectively. Results A total of 39 patients were enrolled (R, n = 23; R + MR, n = 16). After four once-per-week treatments, ORR was 100% (complete response, 67%; partial response, 33%). At median follow-ups of 9.8 years for R and 5 years for R + MR, median PFS were 3 and 5.6 years (P = .26), respectively; median overall survival (OS) was not reached. Estimated 5-year PFS and OS for patients treated with R versus R + MR were 39.1% (95% CI, 23.5 to 65.1) and 95.7% (95% CI, 87.7 to 100) versus 58.9% (95% CI, 38.0 to 91.2) and 85.7% (95% CI, 69.2 to 100), respectively. Nine of 23 patients experiencing relapse had evidence of transformation to aggressive B-cell lymphoma; six of these patients had infradiaphragmatic involvement at study entry. Conclusion R is an active agent in NLPHL. Although responses are not durable in most patients, a significant minority experience remissions lasting > 5 years. R + MR results in a nonsignificant increase in PFS compared with R. R may be considered in the relapsed setting for NLPHL. The potential for transformation of NLPHL to aggressive B-cell lymphoma underscores the importance of rebiopsy and long-term follow-up.

Objectives: In recent years, research has increasingly focused on the microenvironment of classical Hodgkin lymphoma (CHL) as a predictor of treatment outcome. The focus of this study was to assess the interobserver reproducibility in interpreting macrophage-associated immunohistochemistry (IHC) for CD68 and CD163 in a retrospective cohort of 88 patients with CHL. Methods: Staining results were correlated with clinical outcome in all patients and those with a high international prognostic score (IPS). Results: The intraclass correlation (ICC) for the five hematopathologists interpreting the IHC was stronger for CD163 (0.70) than for CD68 (0.50). Using a cutoff of 25% mean macrophage reactivity and including all patients, a statistically significant difference in overall survival (OS) was seen only for CD163 ( P = .0006) and not for CD68 ( P = .414). Patients with a mean CD163 reactivity of 25% or more had a median OS of 71 months vs 101 months for patients with less than 25% reactivity. CD163 retained statistical significance in multivariate analysis. In patients with advanced-stage CHL with high IPS, OS was also significantly worse for those with a mean CD163 reactivity of 25% or higher. Conclusions: Our study confirms previous reports of a prognostic role of tumor-infiltrating macrophages in CHL, but only for CD163. Although most of the literature supports an increasing role of macrophage IHC as a predictor of clinical outcome, successful clinical translation will require a standardized method and reporting system.

Mantle cell lymphoma (MCL), an uncommon and aggressive form of non-Hodgkin lymphoma, typically involves lymph nodes. It usually only secondarily involves extranodal sites. We describe an unusual case of a MCL that presented and relapsed in the earlobes. Light microscopic findings were initially regarded as suggestive of small lymphocytic lymphoma, although subsequent analysis of fresh tissue by flow cytometry led to the diagnosis of MCL. Retrospective application of a broad panel of recently developed markers suitable for analysis of routinely processed tissue yielded results that also permitted a diagnosis of MCL. If these results had been available at the time of initial presentation, they would have obviated the need for rebiopsy. Greater awareness not only of the phenotypic criteria by which lymphomas are classified but of the lymphoma markers available for evaluation of routinely processed tissue should facilitate the accurate diagnosis of diseases like MCL and minimize the risk of misdiagnosis as an indolent disorder.

Introduction: Prior studies have shown preliminary clinical efficacy in combining CpG-ODN with radiation therapy (XRT) to patients with indolent B-cell lymphoma. We report interim Phase 1/2 data of combination XRT and SD-101, a synthetic class C CpG-ODN TLR9 agonist, selected for the strong induction of type I interferon. Methods: This dose-escalation Phase 1/2 trial enrolled patients with untreated indolent B-cell lymphoma having at least 2 measurable lesions (one palpable). The primary endpoints were safety and alpha-interferon-gene induction. Secondary endpoints included efficacy assessment using Cheson (1999) criteria and quantification of changes in tumor-infiltrating lymphocytes. A single lesion was treated with XRT (2 Gy daily X 2 days) followed by a single intratumoral dose of SD-101 (same lesion). 4 additional doses of intratumoral SD-101 were given weekly over next 4 weeks. The treated lesion and distal lesions were monitored during the study. Pharmacodynamic assessment included flow cytometry analysis of immune infiltrates in an FNA sample of the treated tumor and RT-PCR RNA assay of whole blood to assess induction of alpha-interferon genes. Efficacy assessment included imaging (CT at 3, 6, and every 6 months thereafter). Results: As of 01 Aug 2016, 13 patients were treated with escalating doses of SD-101 at 1, 2, 4 or 8 mg/dose. There were no dose limiting toxicities. The majority of related adverse events (AEs) were Grade 1 (mild). The most common were flu-like symptoms (chills, headache, malaise, myalgia), typically resolving within ≤ 48 hours without requiring intervention (e.g., acetaminophen). An induction of alpha-interferon genes occurred at all dose levels with a similar level of induction. For the dose expansion phase, 15 patients were enrolled at 1 mg (6) and 8 mg dose group (9). Similar to dose escalation phase, the most common related events were again flu-like symptoms, typically resolving within ≤ 48 hours mitigated with acetaminophen. There was one dose delay for Grade 3 neutropenia in one patient (1 mg) that resolved following drug interruption. Twenty-nine Grade 3 transient flu-like symptoms were reported for four patients (44%) who received the 8 mg dose (e.g., chills headache, malaise, myalgia, and fatigue). Only one of the four patients experienced all 5 Grade 3 flu-like symptoms after intratumoral injection. There were no grade 4 or serious events reported, and no patient discontinued due to an adverse event. A reduction in tumor sizes was observed in the study over time (see Figure 1). At Day 90 the median changes in the product of diameters from baseline were -46.1% and -10.2% for treated tumor and distal tumors, respectively. At Day 540, the median changes were -68.6% and -24.1%, respectively. In patients with follicular lymphoma (largest subgroup), preliminary data suggest a higher percentage of CD8+ T cells in the treated lesion (FNA at day 8) correlated with an increased abscopal response. Conclusions: Intratumoral SD-101 following radiation therapy has been well tolerated and preliminary efficacy, promising. Abscopal anti-tumor activity was observed with preliminary data suggesting that a higher percentage of CD8+ T cells in the treated lesion correlated with an increased abscopal response seen in follicular lymphoma. Enrollment is ongoing with an option for cycle 2 retreatment. Disclosures Levy: Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Reagan:Seattle Genetics: Research Funding. Friedberg:Bayer: Other: Data Safety Monitoring Committee. Bartlett:Gilead: Consultancy. Leung:Dynavax: Employment. Peterkin:Dynavax: Consultancy. Xing:Dynavax: Employment. Coffman:Dynavax: Employment. Janssen:Dynavax: Employment. Candia:Dynavax: Employment.

Inhibition of CDK4/6 has emerged as a promising therapy for diverse human cancers. Mantle cell lymphoma (MCL), in which aberrant cyclin D1 expression and CDK4 activity underlie unrestrained proliferation of tumor cells, remains incurable. Targeting Bruton tyrosine kinase (BTK) with ibrutinibin recurrent MCLhas unprecedented single agent activity, with a completion remission (CR) rate of 21%. However, progression on ibrutinib is virtually universal in MCL and is associated with aggressive proliferation of tumor cells and a dismal clinical outcome. By longitudinal integrated RNA- and exome-seq analysis, we previously discovered a mutation in the ibrutinib binding site (BTKC481S) in MCL that was specific to relapse from a durable response, but absent in both primary resistance and resistance following a transient response. Irrespective of mechanism, ibrutinib resistance was associated with enhanced PI3K activation as determined by Western blotting of MCL cells isolated from serial biopsies. Induction of prolonged early G1 arrest (pG1) by selective inhibition of CDK4 with palbociclib sensitized to PI3K inhibition independent of this BTK mutation and to ibrutinib when the wild type BTK was retained. In both cases, synergistic killing appears to occur via cooperative inactivation of PI3K. Collectively, our data suggest that dual inhibition of CDK4 and BTK or PI3K restrain the expansion of resistant clones or even eliminate them to deepen or prolong the clinical response to targeting BTK. To test this hypothesis, we initiated a phase I clinical trial of palbociclib plus ibrutinib in recurrent MCL patients in August of 2014. All 5 dose levels included ibrutinib daily and palbociclib administered on days 1-21 of each 28-day cycle (Figure 1). Based on an intent-to-treat analysis of 18 patients, 12 (67%) patients have responded to treatment including 8 (44%) complete responses (CR). The median time to CR was 3 cycles and no responding patients have progressed on study. The therapy was well tolerated (see ASH abstract by Martin et al for clinical information). RNA- and exome-seq were performed to assess the genomic alternations and gene expression on purified MCL cells from samples before therapy, on progression and on treatment from PR patients. Initial analysis did not detect non-synonymous mutation in CDK4, CCND1, or genes in the BCR or PI3K signaling pathway. Hemizygous deletion of Rb, p53, ATM and the INK4A/B locus and amplification of PIK3CA and PIK3CB occurred in 30-50 % of patients before therapy. These copy number variations were predominantly associated with primary resistance (4 subjects) but did not preclude CR or PR. By contrast, expression of PIK3IP1, a putative PI3K inhibitor, was markedly reduced on progression in all primary resistant patients, but not in the PR patient. Function studies demonstrated that PIK3IP1 was required for pG1 sensitization to BTK and PI3K inhibition in MCL cells in vitro. Moreover, PIK3IP1 was induced in pG1 together PI3K inhibition in MCL cells in patients responding to palbociclib alone in a separate clinical trial (Martin, DiLiberto et al, unpublished), suggesting that PIK3IP1 mediates pG1 reprogramming. In summary, the high CR rate and durability support our hypothesis that induction of prolonged early G1 arrest by CDK4 inhibition reprograms MCL cells for deepened and durable targeting of BTK in MCL. Our data further suggest inhibition of PI3K by PIK3IP1 as a potential mechanism to overcome ibrutinib resistance. A phase II multi-center clinical trial is planned to further elucidate the genes and mechanisms that discriminate sensitivity from resistance to dual targeting of CDK4 and BTK. Figure 1. Dual targeting of CDK4 with palbociclib and BTK with ibrutinib in recurrent MCL Figure 1. Dual targeting of CDK4 with palbociclib and BTK with ibrutinib in recurrent MCL Disclosures Blum: Pharmacyclics: Research Funding. Ruan:Pharmacyclics: Research Funding, Speakers Bureau. Martin:Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding.

Background Peripheral T-cell lymphomas (PTCLs) encompass ~10-15% of aggressive non-Hodgkin lymphomas. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or variations thereof, are the most commonly used treatment regimens with complete remission (CR) rates ranging from 39-55% (Reimer 2009, d'Amore 2012). With the exception of low international prognostic index (IPI)-anaplastic lymphoma kinase (ALK)-positive ALCL, with 4-year progression-free survival (PFS) and overall survival (OS) ranging from 25-35% and 30-40%, respectively (Ellin 2014). We previously reported the results of this phase 1 trial that evaluated brentuximab vedotin (BV) administered in sequence with CHOP, or in combination with CHP (CHOP without vincristine) in treatment-naive patients (pts) with CD30-expressing PTCL (NCT01309789). The combination therapy (BV+CHP) showed safety and activity at standard doses, with an objective response rate (ORR) of 100% and complete response (CR) rate of 88% (Fanale 2014). The most common adverse events (AEs) experienced by pts were nausea and peripheral sensory neuropathy (69% each). Four-year durability data and updated results on peripheral neuropathy (PN) resolution from the BV+CHP combination treatment arm are presented herein. Methods Adults with CD30-expressing PTCL, including systemic ALCL (anaplastic large cell lymphoma, ALK-negative, or ALK-positive with IPI score ≥2) were eligible for this study. CD30 expression for non-ALCL pts was defined as ≥1% CD30 expression in malignant cells. Pts on the combination treatment arm received 1.8 mg/kg BV and standard-dose CHP q3wk for up to 6 cycles. Pts who achieved at least a partial response (PR) following treatment could receive continued BV 1.8 mg/kg q3wk as single-agent for up to 10 additional cycles. Antitumor response was assessed by the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Twenty-six previously untreated pts received BV+CHP. Disease diagnoses included systemic ALCL (n=19; including ALK-negative, n=16 and ALK-positive, n=3), PTCL-NOS (n=2), angioimmunoblastic T-cell lymphoma (AITL, n=2), adult T-cell leukemia/lymphoma (ATLL, n=2), and enteropathy-associated T-cell lymphoma (EATL, n=1). Twenty-one of the 26 pts who achieved remission with combination treatment continued on to receive single-agent BV. Overall, the 26 pts received a median of 13 cycles (range, 3 to 16) of BV. After a median observation period of 52 months (range 4.6 to 58.3) from first dose, 18 pts remain on study. The estimated 4-year PFS and OS rates are 52% (95% CI: 31, 69) and 80% (95% CI: 59, 91), respectively. The median PFS has not been reached (95% CI: 12.3, -). To date, 15 of 19 ALCL (3/3 ALK-positive, 12/16 ALK-negative), and 6 of 7 non-ALCL pts were alive at last follow-up. Five pts (19%) received subsequent treatment with single-agent BV in long-term follow-up and 3 pts received stem cell transplants (1 autologous, 2 allogeneic) for relapsed disease. There were no pts who underwent a consolidative stem cell transplant. Of the 26 pts treated with combination therapy, 19 (73%) experienced PN. Of these pts, 95% (18 of 19) experienced complete resolution (8 pts), or some resolution or improvement (defined as a decrease by at least 1 grade from worst grade, 10 pts). Of the pts who experienced improvement, 1 pt each improved from Grade 3 to a lowest Grade 2 and from Grade 3 to a lowest Grade 1, and 5 pts improved from Grade 2 to a lowest Grade 1. The median time to resolution of PN symptoms was 5.7 months. Eleven pts had ongoing neuropathy at last follow-up, of which, 9 pts had Grade 1 severity and 2 pts had Grade 2. Conclusions These 4-year durability results demonstrate that among pts with PTCL, initial therapy with BV in combination with CHP can induce long-term remissions with a tolerable safety profile. A phase 3 randomized trial comparing BV+CHP with CHOP for the frontline treatment of CD30-expressing PTCL is ongoing (NCT01777152). Progression-free Survival Figure Figure. Disclosures Horwitz: Celgene: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Research Funding; Infinity: Research Funding; Huya: Consultancy; FortySeven: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Bartlett:Gilead: Consultancy. Pro:Takeda: Honoraria; Seattle Genetics: Honoraria; Celegene: Honoraria. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Davies:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; GSK: Research Funding; Mundipharma: Honoraria; Janssen: Honoraria; Bayer: Research Funding; Karyopharma: Honoraria, Research Funding; Pfizer: Research Funding. Illidge:Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Uttarwar:Seattle Genetics: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Ren:Seattle Genetics: Employment, Equity Ownership.

Background: In follicular lymphoma (FL) patients treated with first-line R-CHOP, early progression of disease (POD) within 2 years after diagnosis is associated with high risk for death (hazard ratio 6.4) and a 50% 5-year overall survival (Casulo et al. JCO 2015). Whether these observations hold for patients treated without chemotherapy is unknown. The Alliance for Clinical Trials in Oncology conducted three frontline rituximab-based non-chemotherapy-containing biologic immunotherapy doublet clinical trials: R-Galiximab (Anti-CD80, CALGB 50402), R-Epratuzumab (Anti-CD22, CALGB 50701) and R-Lenalidomide (CALGB 50803). We performed a retrospective analysis of 174 patients to determine outcomes of early progressors after initial biologic, non-cytotoxic treatment and risk factors for early POD. Methods: CALGB 50402 (n=60), CALGB 50701 (n=57), and CALGB 50803 (n=57) had similar eligibility criteria: previously untreated follicular lymphoma, grade 1, 2 or 3a with stage III, IV or bulky (single mass >7 cm) stage II disease, and ECOG PS 0 to 2. Early POD was defined as progression within 24 months from study entry. Univariate and multivariate logistic regression modeling using forward selection was performed to identify predictors of early POD. Kaplan-Meier (KM) method was used to estimate 2-year and 5-year overall survival probability. Hazard ratios (HR) and 95% CI were calculated using a univariate and multivariate Cox regression model adjusting for FLIPI. Results: Twenty-seven percent (48/174) of patients had early POD. Median survival follow-up time from study entry was 5.5 years (2.1 to 10.1 years) and median time from diagnosis to enrollment was 2 months (0.2 to 115 months). Median age was 54 (range: 22-90), 49% were male and 24% had low-, 52% intermediate- and 24% high-risk FLIPI (Table 1). Early POD from study entry conferred a worse OS [HR=4.86 (95% CI 1.90-12.4), p < 0.001]. After adjusting for FLIPI, patients with early POD from study entry had a worse OS compared with patients who did not progress within 2 years [HR=4.77 (95% CI 1.70-13.4), p=0.003]. For early POD, the 2-year survival probability was 89% (76-95%) vs. 100% for non-early POD, and the 5-year survival was 76% (60-86%) vs. 99% (95-99%), respectively (Figure 1). When the 2-year early POD interval was taken from time of diagnosis, similar findings were noted (n=171, HR for OS 5.27 (95% CI 1.98-14.0), p 0.0009) [Table 2]. Univariate analysis revealed age >60 (p=0.019), male sex (p=0.002), higher FLIPI (p4 (p=0.010), elevated LDH (p=0.004), nodal size >7 cm (p=0.002), albumin Conclusions: Early relapse within 2 years after diagnosis in patients receiving front-line rituximab-based biologic non-cytotoxic therapy is associated with an increased risk of death. These data are similar to previous findings in patients treated with R-CHOP from the National LymphoCare study, suggesting that the adverse survival of patients with early POD may be independent of systemic treatment modality. Novel clinicopathological approaches are needed at diagnosis to identify patients who are likely to have unfavorable outcomes, and for whom biologic doublets are efficacious. Support: U10CA180821, U10CA180882.ClinicalTrials.gov Identifier: NCT00117975 (CALGB 50402), NCT00553501 (CALGB 50701), and NCT01145495 (CALGB 50803) Disclosures Lansigan: Pharmacyclics: Consultancy; Teva: Research Funding; Celgene: Consultancy; Spectrum: Consultancy, Research Funding. Cheson:Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Czuczman:Celgene: Employment. Martin:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Teva: Research Funding; Acerta: Consultancy; Novartis: Consultancy; Gilead: Consultancy, Other: travel, accommodations, expenses. Hsi:Eli Lilly: Consultancy; Abbvie: Consultancy; Cellerant Therapeutics: Consultancy; Seattle Genetics: Honoraria; HTG molecular diagnostics: Honoraria. Bartlett:Gilead: Consultancy.

Background: Patients (pts) with refractory aggressive non-Hodgkin lymphoma (NHL) have poor outcomes with currently available therapies, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival (OS) of 6.6 months (mo) as demonstrated in the 635 pt SCHOLAR-1 meta-analysis (Crump, ASCO 2016; abstract 7516). ZUMA-1 is the first multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells in refractory, aggressive NHL (NCT02348216). The phase 1 portion of ZUMA-1 showed ongoing CRs at 12+ mos in 43% of pts (Locke, ESMO 2016; abstract 1048O). The pivotal phase 2 portion of ZUMA-1 comprises 2 cohorts based on tumor type: DLBCL (cohort 1) and primary mediastinal B-cell lymphoma or transformed follicular lymphoma (cohort 2). Here, we present results of a prespecified interim analysis from cohort 1. Methods: Pts received a target dose of 2 × 106 anti-CD19 CAR T cells/kg after a low-dose conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily for 3 days. The primary endpoint is objective response rate (ORR) per 2007 IWG criteria. Key secondary endpoints include duration of response, frequency of adverse events (AEs), and levels of CAR T cells and serum cytokines. Key inclusion criteria include age ≥18 years, ECOG performance status (PS) 0-1, and refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤12 mos after autologous stem cell transplant (ASCT). Pts must have received a prior anti-CD20 antibody and an anthracycline-containing regimen. A prespecified interim analysis was to be conducted to determine early efficacy with a nominal alpha level of 0.017 in 50 treated pts in cohort 1 with a minimum follow-up of 3 mos. Results: In total, 111 pts from 22 institutions were enrolled and leukapheresed, and 101 pts received KTE-C19. As of August 24, 2016, 51 pts in cohort 1 were eligible for analysis. Median age was 58 years (range, 25-76), 73% were male, 71% had ECOG PS 1, 78% were refractory to ≥2 lines of therapy, 20% relapsed ≤12 mos of ASCT, and 61% were treated with ≥3 lines of prior therapy. KTE-C19 was successfully manufactured in 99% of pts enrolled. Average turnaround time from apheresis to receipt of KTE-C19 at the clinical site was 17.4 days. With an ORR of 76%, the study met the primary endpoint (P CAR T cells expanded within 14 days of KTE-C19 infusion, and peak expansion was associated with ongoing response at mo 3 (P=0.008). Pts who developed grade ≥3 neurological events had increased serum levels of IL-15 (P=0.0002), IL-6 (P=0.003); IL-10 (P=0.009) and IP-10 (P=0.0003). Cytokines/chemokines returned to baseline levels in most pts by day 28. Data from 93 pts with at least 1 mo of follow-up at the data cutoff will be presented. Conclusions: ZUMA-1 is the first reported multicenter trial of CAR T cell therapy in pts with refractory aggressive NHL. KTE-C19 induced a nearly 6-fold higher CR rate compared to historical outcomes in SCHOLAR-1. Efficacy strongly associated with peak CAR T levels. Central manufacturing, logistics, and AE management were successfully implemented across 22 sites, most with no prior CAR T therapy experience. Results from cohort 2 of ZUMA-1 are also presented (Abstract #998). KTE-C19 demonstrated significant clinical benefit in pts with no curative treatment options. Supported in part by funding from The Leukemia & Lymphoma Society Therapy Acceleration Program®. Drs Neelapu and Locke contributed equally to this study. Disclosures Neelapu: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Locke:Kite: Membership on an entity's Board of Directors or advisory committees. Miklos:pharmacyclics: Research Funding; Kite Pharma: Research Funding; Roche: Research Funding; Novartis: Research Funding. Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Siddiqi:Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Lin:Mayo Clinic: Employment; Janssen: Research Funding. Timmerman:Bristol-Myers Squibb, Kite Pharma, Valor Biopharmaceuticals, Janssen: Research Funding; Seattle Genetics, Genmab, Celgene: Consultancy, Honoraria. Goy:COTA: Membership on an entity's Board of Directors or advisory committees; Janssen/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research funding for clinical trials through institution; Acerta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Other: Research funding for clinical trials through institution. Smith:Abbvie: Research Funding; Celgene: Honoraria; Spectrum: Honoraria; Genentech: Honoraria. Deol:Jazz Pharmaceuticals: Consultancy. Avivi:Tel Aviv Sourasky Medical center: Consultancy, Other: consultancy to :BMS Roche. Westin:Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. Levy:Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Reagan:Seattle Genetics: Research Funding. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership.

Background Single-agent ibrutinib confers a response rate of 77%, including a complete response (CR) rate of 19% in patients with previously treated mantle cell lymphoma (MCL); however, with a median progression-free survival (PFS) of 14.6 months and 1-year response duration (RD) rate of 69%, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK (Chiron et al. Cancer Discovery 2014). We conducted a phase I trial to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. Methods Adult patients who were ibrutinib and CDK4/6 inhibitor-naïve who had previously treated MCL were eligible to participate. The primary objective was to estimate the maximum tolerated dose of the combination. Consenting patients were enrolled to one of five dose levels, shown in Table 1. Patients were treated in 28 day cycles, with ibrutinib administered daily and palbociclib administered on days 1-21. (Table 1). Patients could continue to receive study treatment until progression, unacceptable toxicity, or withdrawal of consent. Doses were escalated according to a standard phase I 3+3 design. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. All CRs, as documented by CT, required confirmation by PET/CT; bone marrow biopsy and endoscopy were also required in patients with known marrow or GI tract involvement, respectively. Additional objectives included pharmacokinetics and evaluation of pretreatment samples for biomarkers of response or resistance. Results From August 2014 to June 2016 a total of 20 patients (15 males, 5 females) were enrolled (DL1 n=3, DL2 n=3, DL3 n=6, DL4 n=3, DL5 n=5). The patients' MIPI risk distribution were 7 low, 7 intermediate, and 6 high. The median number of prior therapies was 1 (range 1-5). Six patients were refractory to their last prior therapy. Three patients experienced dose limiting toxicity: One patient treated at DL3 experienced grade 4 thrombocytopenia lasting more than 7 days, and grade 3 rash was seen in two patients at DL5. Grade 3-4 hematological toxicity included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Grade 3-4 non-hematological toxicity regardless of attribution included one patient with each of the following: lung infection, ALT/AST increase, encephalitis, hyponatremia, sinus tachycardia, pneumonitis. Grade 1-2 adverse events related to treatment and occurring in at least 2 patients included the following: diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%). Other than the two patients that experienced grade 3 rash at DL5, no patients have required dose reductions; 6 patients required dose interruptions. Thirteen subjects continue on study therapy. The reasons for stopping treatment were disease progression (n=4), adverse event (elevated liver enzymes, n=1; and prolonged cytopenias, n=1), and allogeneic stem cell transplantation (n=1). Of the 18 patients that have had at least one response evaluation to date, 12 (67%) patients responded to treatment and 8 (44%) achieved a CR. The median time to CR was 3 cycles and no responding patients have progressed on study. With a median follow up of 11 months, the estimated 1-year PFS and RD are 68% and 100%, respectively (Figure 1). Conclusions The mechanism-based combination of ibrutinib plus palbociclib is well tolerated and active. Toxicity is primarily related to myelosuppression of grade 1-2 severity, although grade 3 rash was observed at the highest doses evaluated. In this small group of patients, the combination produced responses at all dose levels, with a CR rate of 44% and a median time to CR of 3 months. No responding patients have progressed to date. These preliminary CR, PFS, and RD rates appear better than those reported in other studies of single-agent ibrutinib although the numbers of patients was very small. A phase II multi-center clinical trial to evaluate time to progression is planned. Biomarker studies to evaluate mechanisms of primary resistance are ongoing. Disclosures Martin: Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Janssen: Research Funding.

Background: Contemporary approaches to non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) incorporate chemo-immunotherapy, biologic combinations, and immune modulating agents; toxicities in elderly pts (³65 years) receiving these therapies are not well studied. Further, clinical and biologic factors predicting these toxicities in pts receiving biologic therapy remain undefined. Methods: We reviewed data on NHL and/or CLL pts treated prospectively on 14 studies by the Alliance for Clinical Trials in Oncology from 2004-2014 (Table 1). Toxicity was assessed per the NCI CTCAE at the time of trial enrollment, and the probabilities of experiencing grade 3 and grade 4 hematologic (hem) and non-hematologic (non-hem) toxicities were modeled as a function of age (³65 years vs. < 65), time on study, treatment (biologics only vs. biologic + chemotherapy), gender, race, LDH, performance status (PS), stage, and an age-by-treatment interaction using logistic regression. Results: A total of 1199 pts (409 age ³ 65; 790 age < 65; 736=CLL and 463=NHL) were included. Among these patients, 493 received only biologic therapy (166 age ³ 65; 327 age < 65; 104 CLL; 389 NHL), and 706 received biologic + chemotherapy (243 age ³ 65; 463 age < 65; 632 CLL; 74 NHL). Among CLL pts (259 pts ³ 65), the effect of age on the probability of experiencing a grade 3 heme toxicity differed by treatment type (age-by-treatment interaction p = 0.047). Specifically, the adjusted odds ratio (OR) (age ³ 65 vs. < 65) for pts receiving only biologic therapy was 3.075 (95% CI: 1,15-8.25), and that for pts receiving biologic + chemotherapy was 1.044 (95% CI: 0.69 - 1.57). Similar results were seen in CLL pts for grade 4 heme toxicities (age-by-treatment interaction p = 0.033; biologic OR 6.937, 95% CI: 1.76-27.35; biologic + chemo OR 1.484, 95% CI: 1.04-2.13). No such interactions were found in CLL pts for grade 3 and 4 non-hem toxicities; however, older pts had significantly higher odds of experiencing a grade 3 non-hem toxicity than younger pts (adjusted OR 1.40; p = 0.047; 95% CI: 1.004-1.96). No age group differences were found in CLL pts for grade 4 non-hem toxicity. Similar analyses were performed for NHL pts (150 pts ³ 65), but no significant age group differences were found. Among CLL pts, women had significantly higher odds of experiencing a grade 3 heme toxicity than men (OR 2.01; p = 0.0007); no difference in grade 3 non-hem or any grade 4 toxicity was noted. Non-Caucasian CLL pts had higher odds of experiencing a grade 4 non-hem toxicity than Caucasians (OR 2.892; p = 0.0029), but no other toxicity differences were found. Worse PS was associated with increased toxicities (OR 1.871; p = 0.0009: grade 3 heme; OR 1.647; p = 0.0025: grade 3 non-hem; OR 1.410; p = 0.0448: grade 4 heme, and OR 1.931; p = 0.0252: grade 4 non-hem). CLL pts with advanced stage disease had higher odds of experiencing a heme toxicity (grade 3: OR 1.95; p = 0.0007, grade 4: OR 1.451; p = 0.0329), but no stage associations were found for non-hem toxicities. Among NHL pts, men had significantly higher odds of experiencing a grade 4 hematologic toxicity than women (OR 4.351; p = 0.0169), but no other toxicity differences were found. An increase in LDH was associated with significantly higher odds of experiencing grade 3 non-hem and grade 4 heme toxicities (grade 3 non-heme: OR 1.633; p = 0.021, grade 4 heme: OR 2.039, p = 0.0182), but no such effect was found for grade 3 heme or grade 4 non-hem. Worse PS was associated with higher odds of experiencing grade 3 toxicities (heme: OR 2.025; p = 0.0344, non-hem: OR 2.458; p = 0.0013), but no such differences were found for grade 4 toxicities. No significant stage or race effects were found in NHL patients. Conclusion: In pts ³65 years who have CLL or NHL, we identified several clinical and disease-related factors as potential predictors of developing grade 3 and/or 4 heme and non-hem toxicities (Table 2). A prognostic model is being constructed to predict toxicities in these under-studied pts to guide management and monitoring. Further, the impact of these toxicities on outcomes is being analyzed and will be presented at the meeting. Disclosures Hurria: Celgene: Other: Research; Optum Health Care SOlutions: Consultancy, Other: Conference panel, research; Boehringer Ingelheim Pharmaceuticals: Consultancy; Sanofi: Consultancy; Carevive: Consultancy; Novartis: Other: Research; GTx, Inc: Consultancy. Bartlett:Gilead: Consultancy. Cheson:Gilead: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nabhan:Infinity: Consultancy; Abbvie: Consultancy; Cardinal Health: Consultancy; Seattle Genetics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Research Funding; Celgene Corporation: Consultancy, Research Funding.

Background: ZUMA-1 is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in patients with refractory aggressive B-cell non-Hodgkin lymphoma. In phase 1, KTE-C19 demonstrated ongoing complete remissions with a tolerable safety profile (Neelapu, ASCO 2016). The phase 2 portion of the study has 2 cohorts based on tumor type: diffuse large B-cell lymphoma (cohort 1) or PMBCL/TFL (cohort 2). Results from cohort 2 at the time of the first pre-specified interim analysis of ZUMA-1 are presented here. Methods: Patients received KTE-C19 at a target dose of 2 × 106 (minimum 1 × 106) anti-CD19 chimeric antigen receptor (CAR) T cells/kg after a low-dose conditioning chemotherapy regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily for 3 days. The primary endpoint was overall remission rate per International Working Group criteria (Cheson, J Clin Oncol2007). Key secondary endpoints include duration of response, incidence of adverse events (AEs), levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria include ≥ 18 years old, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and chemorefractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤12 months after autologous stem cell transplant. Patients must have received prior anti-CD20 therapy and an anthracycline-containing regimen. Results: As of June 16, 2016, six patients in cohort 2 were treated with KTE-C19 and had at least 30 days of follow up. The median follow up time was 3.2 months. Fifty percent of patients had PMBCL and 50% had TFL. Median age was 55 years (range, 28-60), 67% were male, 67% ECOG performance status 0, and 50% were refractory to second or greater line of chemotherapy while 50% relapsed after autologous stem cell transplant. The objective response rate was 100%. All patients have ongoing complete remissions. Worst grades 3 and 4 treatment-emergent AEs occurred in 17% and 67% of patients, respectively. There were no grade 5 events. All grade 4 treatment-emergent AEs were cytopenias. KTE-C19-related worst grade 3 and 4 AEs occurred in 50% and 17% of patients, respectively. Patient incidence of any grade/grade 3/grade 4 CRS and neurotoxicity were 100%/0%/0% and 67%/33%/0%, respectively. All KTE-C19-related AEs have resolved. Biomarker endpoints will be presented. Conclusions: KTE-C19 demonstrated early promising activity in patients with refractory PMBCL and TFL. The predominant toxicities of CRS and neurotoxicity were generally reversible. Updated trial results from 11 patients at interim analysis 2 will be presented. Clinical trial: NCT02348216. This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program® Disclosures Locke: Kite: Membership on an entity's Board of Directors or advisory committees. Bartlett:Gilead: Consultancy. Siddiqi:Pharmacyclics, LLC, an AbbVie Company: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; Kite pharma: Other: Funded travel, 1 day registration, and 1 night hotel stay for EHA2016 so I could present trial data there. . Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Westin:ProNAi: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. LaCasce:Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Forty Seven: Consultancy; Forty Seven: Consultancy. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership.

Background: Diffuse large B-cell lymphoma (DLBCL) is comprised of multiple diseases with different outcomes, cell of origin and molecular pathogenesis. DLBCL derived from germinal center B-cells (GCB) and activated B-cells (ABC) constitutes over 80% of DLBCL. A small number of DLBCL tumors harbor MYC translocations, which are associated with a poorer prognosis. Primary mediastinal B-cell lymphoma (PMBL) occurs in younger patients and is typically treated with intensive or combined modality therapy. R-CHOP is the standard of care for DLBCL but has not been prospectively studied within DLBCL molecular subtypes. DA-EPOCH-R is an alternative and more dose-intensive regimen that showed a PFS of 81% at 4-years in a phase II multicenter CALGB study (Haematologica 2012; 97:758). CALGB/Alliance undertook a phase III randomized study to compare R-CHOP and DA-EPOCH-R in DLBCL and specifically within the GCB and ABC subtypes. Methods: Patients had stage II or higher newly diagnosed DLBCL, age ≥ 18 years and were HIV negative. Subjects were randomized 1:1 to receive R-CHOP or DA-EPOCH-R as previously published. Central nervous system prophylaxis in at-risk patients was 12 mg intrathecal methotrexate in cycles 3-6 (4 doses total). All subjects with accessible tumor were required to have a biopsy or waiver. Subjects received a total of 6 treatment cycles. The primary study endpoints were EFS of R-CHOP (Arm A) versus DA-EPOCH-R (Arm B) and to develop a molecular predictor of outcome based on GCB and ABC DLBCL. Additional analyses include toxicity, pharmacogenomics and analysis of tumor genetics by next generation sequencing, and. Results: 524 patients registered (262 on each arm) between May 2005 and May 2013. Efficacy analysis includes R-CHOP (n=233) and R-EPOCH (n=231) assigned patients with confirmed eligibility who received any treatment. Characteristics of patients registered to Arm A and B did not differ with median age (58; 56), male sex (53.2%; 53.7%), high-intermediate/high IPI (33.6%; 38.2%) and primary mediastinal B-cell lymphoma histology (6.9%; 5.2%). Therapy was completed per protocol in 89% and 83%, respectively, for Arm A and B, and disease progression on therapy was 2.6% and 1.7%. Adverse side effects leading to treatment discontinuation were 1.7% and 5.6%, respectively, for Arm A and B. Arm B compared to Arm A was associated with more grade 4 neutropenia (90%; 56%), grade 4 thrombocytopenia (35%; 6%), grade 3/4 febrile neutropenia (37%; 19%) and grade 3 neuropathy (motor: 8%;1% and sensory: 15%; 3%). Grade 5 events on study were the same in both arms. Preliminary analysis of EFS in confirmed eligible subjects shows no difference between Arm A and B with hazard ratio of 1.02 and p=0.89 at a median follow-up of 4.9 years. Overall survival is also similar with hazard ratio of 1.19 and p=0.40 at median 5.0 years. Additional analyses of EFS and OS by age (=60) and by GCB versus ABC DLBCL are in process. Conclusions: There was no difference in EFS or OS between R-CHOP and DA-EPOCH-R when considering all patients. DA-EPOCH-R showed increased toxicity consistent with higher dose-intensity but not increased grade 5 toxicity. Compared to R-CHOP, more patients on DA-EPOCH-R did not complete treatment, which may reflect patterns of care or toxicity. Due to the clinical and genetic diversity of DLBCL, subset analyses are necessary to determine the effect of CNS relapse, GCB and ABC subtypes, age and IPI on outcomes of the two arms. These data do not address the efficacy of these regimens in PMBL or MYC+ DLBCL due to their low frequency, and where more dose-intense regimens appear to be important. Full molecular analyses are ongoing. Support: U10CA180821, U10CA180882, U10CA180888, CA180799, CA180820, CA180833, CA21076, CA21115.ClinicalTrials.gov Identifier: NCT00118209. Disclosures Hsi: Cellerant Therapeutics: Honoraria, Research Funding; Eli Lilly: Research Funding; Abbvie: Honoraria, Research Funding; Seattle Genetics: Honoraria, Speakers Bureau; HTG Molecular Diagnostics: Consultancy, Honoraria. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Bartlett:Gilead: Consultancy. 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. Zelenetz:Gilead Sciences: Research Funding.

Introduction : Rituximab-CHOP (R-CHOP) has resulted in significantly improved outcomes for patients (pts) with untreated DLBCL. Despite this progress, approximately 30% of pts are not cured with R-CHOP, especially those with high risk disease as defined by the IPI. Polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) designed for the targeted delivery of the potent microtubule inhibitor MMAE to cells expressing CD79b. Because ADCs may possess a therapeutic index superior to that of many systemically administered chemotherapies, PoV has the potential to replace vincristine with a targeted agent and potentially increase the potency of the standard R-CHOP regimen. We report preliminary results from the dose-escalation portion of this Phase Ib/II study of PoV combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) (ClinicalTrials.gov [NCT01992653][1]). Methods : This multicenter, open-label study will evaluate the safety, tolerability, and pharmacokinetics of escalating doses of PoV with standard doses of R-CHP. Adults, ages 60-80 years, with newly diagnosed or relapsed/refractory B-cell NHL were given PoV intravenously 1.0, 1.4, or 1.8 mg/kg with R-CHP every 21 days for a total of 6 or 8 cycles. Doses were escalated in a 3+3 design based on dose limiting toxicity assessment during cycle 1. Assessments for anti-tumor activity were performed following 4 cycles of study treatment (tx) and at the end of study tx (EOT). Results: 13 pts (46% male) enrolled in the R-CHP + PoV dose-escalation phase of the study. Median age was 68 years (range 60-73). Pts had untreated DLBCL (n=10), relapsed FL (n=2), and untreated MZL (n=1). At baseline, pts had stage I/II (5), III/IV (8) disease and ECOG status of 1-2 (6). Of 10 DLBCL pts, 4 had age adjusted IPI (aaIPI) 2, and 6 had aaIPI 0-1. At the time of this report, all pts in the 1.0 mg/kg (n=3), 1.4 mg/kg (n=3) and 4 of 7 pts in the 1.8 mg/kg cohort completed study tx. The most common adverse events (AEs) in >3 pts were nausea (8), fatigue (7), diarrhea (6), neutropenia (5), dizziness (4), peripheral neuropathy (PN; 4), and insomnia (4). Across all dose levels, 8 pts had a total of 18 grade (Gr) 3/4 AEs including neutropenia (10), thrombocytopenia (1), febrile neutropenia, pneumonia (2 each), DVT, PE, and ophthalmic herpes zoster (1 each). Six pts experienced a serious AE (SAE). Four pts in the 1.8 mg/kg cohort had SAEs: 1 pt with Gr 2 dysphagia (not attributed to tx), 1 pt with Gr 4 pulmonary embolism (PE) and neutropenia and Gr 3 pneumonia (all tx-related), 1 pt with 2 episodes of Gr 4 neutropenia (tx-related that investigator deemed life-threatening), and 1 pt with Gr 4 pneumonia (not attributed to tx). The PE event was determined to be a DLT by the investigator. This pt had a concurrent event of deep vein thrombosis (non-serious). Seven of 13 pts experienced PN (Gr 1 [n=6] and Gr 2 [n=1]). The pt who had the Gr 2 PN received 2.4 mg/kg of PoV with R-CHP in error for 4 cycles and had additional risk factors for PN including history of diabetes mellitus, prior vincristine therapy. One tx discontinuation due to AE occurred due to Gr 2 PN in this pt who received PoV 2.4 mg/kg. One pt had a dose reduction for Gr 3 neutropenia. No deaths were reported. Of the 10 pts with DLBCL, 8 were assessed for interim response by PET/CT: 5 CR [1 at 1.0 mg/kg, 3 at 1.4 mg/kg, and 1 at 1.8 mg/kg], 3 PR [1 at 1.0 mg/kg and 2 at 1.8 mg/kg]). Two of 10 had not completed 3 cycles of tx and therefore not assessable for interim response. At the EOT, 7 were assessed for response: 5 CR (1 at 1.0 mg/kg, 3 at 1.4 mg/kg, and 1 at 1.8 mg/kg), 1 PR (at 1.0 mg/kg), 1 unevaluable (at 1.8 mg/kg). The 3 other pts were not assessed because they did not have a PET scan at EOT. Of the 2 pts with FL: one had SD (1.0 mg/kg) and one was not evaluable at the time of this report (2.4 mg/kg) at the EOT. One pt with MZL had CR at the EOT, then progressed at month 3 follow-up with biopsy proven transformed DLBCL. Conclusions: Early results show that PoV plus R-CHP has an acceptable safety profile in pts with previously untreated DLBCL. The PoV doses tested (1.0, 1.4, and 1.8 mg/kg) in this study showed acceptable toxicity in previous studies with relapsed NHL pts. Although the protocol-specified MTD was not formally reached, the recommended phase 2 dose of PoV was established at 1.8 mg/kg based on the overall safety and tolerability profile at that dose. The study's Phase 2 PoV+R-CHP expansion and the Phase Ib PoV+obinutuzumab-CHP dose escalation are ongoing. Disclosures Bartlett: AstraZeneca: Research Funding; Janssen: Research Funding; ImaginAb: Research Funding; Pharmacyclics: Research Funding; Genentech, Inc.: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Medimmune: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy. Off Label Use: Polatuzumab vedotin is an investigational agent and not approved for DLBCL. Chen: Genentech, Inc.: Consultancy, Other: Advisory Board; Seattle Genetics: Consultancy, Other: Advisory Board; Janssen: Consultancy, Other: Advisory Board; Gilead: Consultancy, Other: Advisory Board. Kolibaba: Seattle Genetics: Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Acerta: Research Funding; Genentech, Inc.: Research Funding; Novartis: Research Funding; Cell therapeutics: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Amgen: Research Funding; Pharmacyclics: Research Funding. Jones: Genentech, Inc.: Employment. Hirata: Genentech, Inc.: Employment, Equity Ownership. Sharman: TG Therapeutics, Inc.: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Roche: Research Funding; Janssen: Research Funding; Calistoga: Honoraria. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01992653&atom=%2Fbloodjournal%2F126%2F23%2F2726.atom

Background Systemic anaplastic large cell lymphoma (ALCL) is a CD30-expressing subtype of peripheral T-cell lymphoma (PTCL). Approximately 40 to 65% of ALCL patients (pts) will develop recurrent disease after frontline treatment, with median overall survival (OS) and progression-free survival (PFS) after relapse of 5.5 and 3.1 months (mos) (Savage 2008, Mak 2013). We have previously reported results of a pivotal phase 2 study of brentuximab vedotin in pts with relapsed or refractory (R/R) systemic ALCL (NCT00866047). Efficacy was demonstrated with an objective response rate (ORR) per investigator of 86% and a complete response (CR) rate of 66%. Peripheral sensory neuropathy was the most common adverse event (AE), experienced in 41% of pts. Herein, we present the end-of-study results with updated data on response durability and peripheral neuropathy (PN) resolution. Methods Fifty-eight pts with R/R systemic ALCL, ALK-positive or ALK-negative, received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the ORR per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Long-term follow-up to evaluate disease status was assessed per the investigator every 3 mos for 2 years, every 6 mos through Year 5, and annually thereafter. CT scans were required if progression was suspected clinically. Pts who experienced PN were followed for symptom improvement/resolution until approximately 3 years into long-term follow-up. Results The estimated 5-year OS and PFS for all enrolled patients was 60% (95% CI: 47%, 73%) and 39% (95% CI: 25%, 52%), respectively. At study closure, which occurred 5 years after the last patient's end-of-treatment (EOT) visit, the median OS was not reached (95% CI: 21.3, -), and the median PFS was 20 mos (95% CI: 9.4, -). Pts were observed for a median of 71.4 mos (range, 0.8 to 82.4) from first dose. Of the pts who achieved a CR per investigator (38 of 58, 66%), the median OS (endpoints of 95% CI not estimable) and PFS (95% CI: 21.3, -) were not reached. Median OS for pts who achieved partial response per investigator (PR, 12 of 58, 21%) was 11.6 mos (95% CI: 3.1, -). Median duration of objective response was 25.6 mos (95% CI: 11.8, - [range, 0.9 to 79.7+]) and was not reached for CR pts (95% CI: 20.0, - [range, 0.9 to 79.7+]). Of the 58 enrolled pts, 42 (72%) had ALK-negative disease. Median PFS for ALK-negative and ALK-positive ALCL was 20 mos (95% CI: 6.7, -) and 25.5 mos (95% CI: 8.0, -) respectively, with the median OS not reached for each. The estimated 5-year OS was 61% (95% CI: 47%, 76%) for ALK-negative and 56% (95% CI: 32%, 81%) for ALK-positive pts. Of the 38 CR pts, 16 received a consolidative stem cell transplant (SCT, 8 allogeneic, 8 autologous). Median PFS was not reached in these pts who underwent transplant. Median PFS for the CR pts that did not undergo transplant was 39.4 mos (95% CI: 14.3, -). Sixteen pts, with a median observation time of 75.4 mos (range 69 to 82.4), remained in remission at the end of the study without the start of new therapy other than consolidative SCT. Among these pts, 8 received a consolidative SCT, and the remaining 8 pts (14% of all enrolled pts) remained on study and in remission without any additional therapy after single-agent brentuximab vedotin. Thirty-three pts (57% of enrolled pts) experienced PN. Thirty pts (30 of 33, 91%) experienced resolution or improvement, of whom, 22 (67%) reported complete resolution, and 8 (24%) reported some resolution or improvement at last assessment. Of the 11 pts with ongoing neuropathy at last follow-up, 8 pts had Grade 1 severity and 3 pts had Grade 2. Conclusions These end-of-study results demonstrate that among pts with R/R systemic ALCL, the majority of pts have achieved clinically significant durable remissions, and a subset may have been cured with single-agent brentuximab vedotin. Furthermore, associated toxicities are manageable, with high rates of resolution for PN, the most common toxicity associated with brentuximab vedotin. A randomized phase 3 trial is ongoing to evaluate the combination of brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-expressing peripheral T-cell lymphomas, including systemic ALCL (NCT01777152). Overall Survival and Progression-Free Survival Figure. Figure. Disclosures Pro: Takeda: Honoraria; Seattle Genetics: Honoraria; Celegene: Honoraria. Brice:Gilead: Honoraria; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Seattle Genetics: Research Funding; Bristol Myers-Squibb: Honoraria; Roche: Honoraria. Bartlett:Gilead: Consultancy. Rosenblatt:University of Miami: Employment; Seattle Genetics: Research Funding. Illidge:Takeda Pharmaceuticals International Co.: Consultancy, Honoraria; Seattle Genetics: Consultancy, Research Funding. Matous:Seattle Genetics: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Connors:Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; NanoString Technologies: Research Funding. Fenton:Seattle Genetics: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Pinelli:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria; Novartis: Research Funding; SPECTRUM: Consultancy, Research Funding; BMS: Consultancy, Honoraria.

Introduction Brentuximab vedotin (BV) is an ADC directed against CD30, a receptor expressed by malignant Reed-Sternberg (RS) cells present in the inflammatory/immune cell microenvironment of classical Hodgkin lymphomas (cHL). Through induction of immunogenic cell death, BV may prime an antitumor immune response via microtubule disruption of CD30-expressing RS cells (Gardai 2015). Tumor cells expressing PD-1 ligands use the PD-1 pathway to evade an immune response. Nivolumab (Nivo) blocks the PD-1 receptor, inhibits binding of PD-1 ligands, and restores an effective antitumor immune response. Targeted killing of CD30-expressing RS cells, concurrent with restoration of the immune response, may lead to higher complete response (CR) rates in patients (pts) with relapsed or refractory cHL (R/R HL), as well as improved durability of responses post autologous stem cell transplant (ASCT). Here we present updated results from the phase 1/2 study of BV + Nivo in pts with R/R HL. Methods BV + Nivo was evaluated in cHL that had relapsed or was refractory to frontline (FL) chemotherapy in adult pts (NCT02572167). Pts were excluded if they had received prior salvage therapy, BV or immuno-oncology therapy, or allogeneic SCT or ASCT. Pts were treated in 21-day cycles for up to 4 cycles. In Parts 1 and 2 of the trial, BV (1.8 mg/kg) was given on Cycle 1 Day 1 and Nivo (3 mg/kg) on Cycle 1 Day 8. For Cycles 2-4, BV and Nivo were given on Day 1. After the Cycle 4 response assessment, pts were eligible to undergo ASCT. The investigators assessed response per the Lugano Classification (Cheson 2014). Results 62 pts with R/R HL were enrolled in Parts 1 and 2; 61 pts received BV + Nivo, of whom 58 completed treatment (tx). 4 pts discontinued the study due to pt decision (2), AE (1), and investigator decision (1). Median age was 36 years, 52% were female, and 90% had received FL ABVD. 45% of pts had primary refractory disease and 31% experienced relapse within 1 year of FL therapy. Infusion-related reactions (IRRs) occurred in 41% of pts. Tx emergent AEs occurred in 98% of pts prior to ASCT (33% G3, 5% G4). Excluding IRRs, potential immune-related AEs (IrAEs) occurred in 84% of pts (10% G3, 3% G4) with 5 pts (8%) treated with systemic steroids for G4 pneumonitis, G4 pneumonitis and colitis, G2 pneumonitis, G3 diarrhea and G2 colitis, and G3 AST elevation. Among the 60 efficacy-evaluable pts, the CR rate was 62%, (48% of CR pts had Deauville ≤ 2) with an objective response rate of 85%; 5 pts (8%) had stable disease and 4 pts (7%) progressed on tx. At the time of this analysis, 39 pts had initiated ASCT with a median 5.1x106 CD34+ cells/kg (range; 3-60) collected. Median times to neutrophil and platelet engraftment were 12 and 15 days, respectively. Pts were followed for a median of 3 months from ASCT (N=39, range; 0-12) and 5.7 months from first dose (N=61, range; 1-17). BV and Nivo effects on the immune system were evaluated by peripheral blood immunophenotyping, serum cytokine/chemokine analyses, T-cell receptor sequencing, and intracellular cytokine staining. The first dose of BV resulted in elevation of pro-inflammatory cytokines and chemokines and concurrent reduction in serum TARC levels, with these results maintained post Nivo. We observed a reduction in Tregs and other T cell subsets after the first dose of BV with an elevation of T cell subsets post BV + Nivo. While TCR clonality in the periphery did not change over the course of the trial, T cell clonal expansion was observed post BV + Nivo, concurrent with T cell elevation measured by flow cytometry. Ex vivo peptide stimulation of PBMCs isolated from blood revealed the enhanced ability of T cell subsets to respond to MHC I and MHC II antigens following BV + Nivo compared to baseline: e.g., effector memory CD8+ T cells from some pts displayed increased intracellular IL-2, and TNFa after stimulation with MHCI and MHCII peptide pools compared to baseline, potentially indicating elevated activation status of the immune system following combination tx. Conclusion R/R HL remains an unmet clinical need despite recent medical advances. These data suggest the combination BV + Nivo is a well tolerated and an active salvage therapy with a high rate of CR (62%) that has no adverse impact on stem cell collection. The safety and activity of this novel combination support further exploration in an ongoing pivotal phase 3 trial in pts with R/R HL who have either already received or are considered ineligible for ASCT (NCT03138499). Disclosures Herrera: Seattle Genetics: Research Funding; Merck: Consultancy; Genentech: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy. Moskowitz: Seattle Genetics: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Research Funding; ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding. Bartlett: Novartis: Research Funding; ImaginAB: Research Funding; Astra Zeneca: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Vose: Merck: Research Funding; Kite: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Allos Therapeutics: Research Funding; Acerta: Research Funding; Incyte: Research Funding; Onyx: Research Funding; Seattle Genetics: Research Funding; US Biotest: Research Funding; Bristol-Myers Squibb: Research Funding. Ramchandren: Seattle Genetics: Consultancy; MERCK: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Feldman: AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Kite Pharma: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. LaCasce: BMS: Consultancy; Forty Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding. Ansell: Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding. Moskowitz: Celgene: Consultancy; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding. Fenton: Seattle Genetics: Employment, Equity Ownership. Ogden: Seattle Genetics: Employment, Equity Ownership. Taft: Seattle Genetics: Employment, Research Funding. Zhang: Seattle Genetics: Employment, Research Funding. Kato: Bristol-Myers Squibb: Employment, Equity Ownership; Seattle Genetic: Research Funding. Campbell: Seattle Genetics: Employment, Equity Ownership; CTI BioPharma: Employment, Equity Ownership. Advani: Agensys: Research Funding; Pharmacyclics: Research Funding; Regeneron: Research Funding; FortySeven: Research Funding; Nanostring: Consultancy; Celgene: Research Funding; Pharmacyclics: Consultancy; Merck: Research Funding; Juno Therapeutics: Consultancy; Kura: Research Funding; Janssen: Research Funding; Millennium: Research Funding; Seattle Genetics: Research Funding; Gilead: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum: Consultancy; Bayer Healthcare Pharmaceuticals: Research Funding; Infinity: Research Funding; Genentech: Research Funding; Cell Medica: Research Funding; Sutro: Consultancy.

Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

Background: Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) occurs primarily in older patients (pts) who often have increased comorbidities and cannot tolerate aggressive treatments, which leads to poorer outcomes (Balducci, Cancer Control 2015; Thurmes, Leuk Lymphoma 2008). Alkylating agents, such as chlorambucil (clb), have been commonly used to treat these pts (Eichhorst, Blood 2009). Ibrutinib (ibr), a first-in-class, once-daily, inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. RESONATE-2 (PCYC-1115) is a randomized phase 3 trial designed to compare the efficacy and safety of ibr vs clb in pts with treatment-naïve (TN) CLL/SLL (Tedeschi, ASH 2015). Primary results, as assessed by an independent review committee (IRC), demonstrated with a median follow-up of 18.4 mo that ibr significantly reduced the risk of progression or death by 84% (P Methods: Eligible pts with TN CLL/SLL aged ≥65 y were randomized 1:1 to receive 420 mg ibr daily until progression or 0.5 mg/kg clb (max 0.8 mg/kg) on days 1 and 15 of a 28-d cycle for up to 12 cycles. Pts with del17p were excluded. Pts were stratified by ECOG status and Rai stage. The primary endpoint was PFS per iwCLL 2008 criteria, with 2012 clarification for treatment related lymphocytosis. Secondary endpoints included OS, ORR, rate of hematologic improvement, and safety; longer term follow-up safety data focused on ibr. Pts in the 1115 study with progressive disease (PD) were enrolled in the PCYC-1116 extension study. At 1115 study closure, all pts in 1115 rolled over to 1116. Pts on the clb arm with PD could cross-over to ibr or investigator's choice. Results: Median age of the 269 pts was 73 y (70% ≥70 y). Baseline characteristics were balanced between arms; 45% had advanced Rai stage, 20% had del11q, and 69% had comorbidities at baseline, including CIRS score >6, reduced creatinine clearance, or ECOG performance status of 2. With a median follow-up of 28.6 mo, prolongation of PFS for ibr vs clb was sustained (89% vs 34% at 24-mo; HR, 0.121; 95% CI 0.074-0.198; P Conclusions: With a median time on study of 28.6 mo, ibr continued to have substantial efficacy, with 88% reduction in risk of progression or death. Furthermore, the quality of responses has improved over time, with 18% of CLL/SLL pts achieving a CR/CRi with single agent ibr. Treatment limiting AEs decreased in frequency with longer follow-up, with 79% of this elderly pt population continues daily ibr. Lastly, even with a high rate of cross-over in the clb arm, OS remains significantly improved for pts randomized to ibr. Disclosures Barr: AbbVie: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding. Robak:AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Owen:Gilead: Honoraria, Research Funding; Janssen: Honoraria; Lundbeck: Honoraria; Roche: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria; Celgene: Honoraria; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Bairey:Janssen: Consultancy. Bartlett:Gilead: Consultancy. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Roche: Other: Travel, Accommodations, Expenses. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Coutre:AbbVie: Research Funding; Pharmacylics, LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy. Devereux:Roche: Consultancy, Other: Travel, Accommodations, Expenses ; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. McCarthy:Roche: Consultancy, Other: Travel, Accomodations, Expenses; Chugai: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Simpson:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Offner:Novartis: Consultancy; GSK: Consultancy. Zhou:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Styles:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Kipps:Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau. Ghia:Janssen: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy; Roche: Consultancy, Research Funding; GSK: Research Funding; AbbVie: Consultancy; Adaptive: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau.

Introduction: Rituximab-CHOP (R-CHOP) remains the standard of care for patients with previously untreated DLBCL. Approximately 40% of patients are not cured with R-CHOP; thus, new therapies are needed. Obinutuzumab (GA101, G) is a glycoengineered type II anti-CD20 monoclonal antibody with improved direct cell death and antibody-dependent cell-mediated cytotoxicity compared to rituximab, and may have improved outcomes in certain patient subsets (Vitolo, ASH 2016). In addition, polatuzumab vedotin (pola) is an antibody drug conjugate (ADC) designed to deliver the potent microtubule inhibitor MMAE to cells expressing CD79b. Thus, pola has the potential to replace vincristine with a targeted agent (Tilly, ICML 2017). The dose escalation phase established a recommended phase 2 dose (RP2D) of pola at 1.8 mg/kg. We report updated results for this multicenter, open-label Phase Ib/II study of pola combined G-CHP at the RP2D (ClinicalTrials.gov NCT01992653). Methods: In the dose escalation phase of this study, patients aged 18-80 years, with newly diagnosed or relapsed/refractory B-cell NHL with IPI 0-5 and ECOG 0-2 were given pola intravenously, 1.4 or 1.8 mg/kg, with G-CHP every 21 days for a total of 6 or 8 cycles. Standard doses of CHP and G (1000 mg on days 1, 8, and 15 in cycle 1, and 1000 mg on day 1 of each subsequent cycle) were used. In the dose expansion phase, pola was given at 1.8 mg/kg and patients were restricted to those with previously untreated DLBCL with IPI 2-5. Assessments for anti-tumor activity by Cheson 2007 were performed following 4 cycles of study treatment and at the end of study treatment (EOT). Results: Enrollment in this arm has completed. As of March 31, 2017, 21 patients with previously untreated DLBCL (57% male) had been enrolled to receive G-CHP + pola at 1.8 mg/kg. The median age was 67 years (range 28-76). At baseline, patients had stage I/II (n=3), III/IV (n=18) disease and ECOG status of 0-1 (n=17). At screening, the IPI distribution was: IPI 0-1: 3 patients (14%); IPI 2: 10 patients (48%); IPI 3: 4 patients (19%); and IPI 4: 4 patients (19%). At the time of this report, all patients had completed treatment. The adverse events (AE) across all grades that occurred in > 30% of patients and Grade 3/4 AEs that occurred in more than one patient are presented in Table 1. Table 1: Common Adverse Events and Grade 3/4 Adverse Events Table.jpg Nine patients (43%) experienced 31 serious AEs including febrile neutropenia (29%), neutropenia (10%), pneumonia (10%), C. difficile (5%), sepsis (5%), septic shock (5%), coronary artery disease (5%), supraventricular tachycardia (5%), hyperglycemia (5%), vomiting (5%), asthenia (5%), syncope (5%), mental status change (5%), and acute kidney injury (5%). The septic shock was a grade 5 AE. Eight patients (38%) experienced peripheral neuropathy; 6 (29%) with grade 1 and 2 (10%) with grade 2; no patients experienced peripheral neuropathy of grade 3 or above. 4 patients (19%) discontinued study treatment early due to AE for the following reasons: thrombocytopenia after Cycle 1, fatal septic shock after Cycle 4, coronary artery disease after Cycle 4, and febrile neutropenia after Cycle 5. Efficacy by EOT PET-CT demonstrated overall response of 91% with 81% CR and 10% PR. The two patients without response were unevaluable, both discontinuing prior to response assessment due to AE (thrombocytopenia, septic shock). No responders had any evidence of relapse at time of this analysis with a median study duration of 10 months. Conclusions: The novel combination of pola at 1.8 mg/kg plus G-CHP is active in previously untreated DLBCL and well tolerated.As expected, the main toxicities were related to neutropenia and peripheral neuropathy. Download : Download high-res image (119KB) Download : Download full-size image Table1 . Disclosures Forero-Torres: Roche: Research Funding; Genentech: Research Funding. Kolibaba: TG Therapeutics: Honoraria, Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Gilead Sciences, Inc: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Research Funding; Cell Therapeutics: Research Funding; Acerta: Research Funding. Tilly: Gilead: Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Honoraria. Salles: Gilead: Consultancy, Other: Advisory board; Celgene: Consultancy, Other: Advisory board; Janssen: Consultancy, Other: Advisory board; Bristol-Myers Squibb: Consultancy, Other: Advisory board; Amgen: Consultancy, Other: Advisory board; Kite: Consultancy, Other: Advisory board; Merck: Consultancy, Other: Advisory board; Morphosys: Consultancy, Other: Advisory board; Novartis: Consultancy, Other: Advisory board; Roche: Consultancy, Other: Advisory board, Research Funding; Servier: Consultancy, Other: Advisory board. Wang: Genentech, Inc.: Consultancy, Employment. Lee: Genentech, Inc.: Employment. Sharman: Acerta: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Other: GIBB is sponsored by Genentech Inc. Third-party editorial support, under the direction of Anthony Masaquel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding; TG Therapeutics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

BACKGROUND To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III–IV or bulky Stage II disease, and an ECOG performance status of 0–1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3–4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m2 on Day 1 and etoposide 100 mg/m2 on Days 1–3 with doxorubicin 50 mg/m2 on Day 1, vincristine 1.4 mg/m2 (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1–5. With the addition of G-CSF at 200 μg/m2 on Days 5–19, the MTD was cyclophosphamide 1500 mg/m2 and etoposide 160 mg/m2 on Days 1–3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 μg/m2 to 400 μg/m2 did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23–39) and 48% (95%CI, 40–57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17–52) and 51% (95%CI, 33–70), respectively. CONCLUSIONS Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP. Cancer 2001;92:207–17. © 2001 American Cancer Society.

Non-Hodgkin's lymphomas (NHL) encompass a heterogeneous group of lymphoid malignancies with varying natural histories and prognoses. Recent classifications for NHL have defined distinct lymphoma entities based on morphology, immunophenotype, genetic features, clonal cell lineage and clinical features. These new, more precise classifications and characterizations of NHL will be essential in developing new targeted therapies. However, for this brief review, we will continue describe NHL primarily as indolent or aggressive. Treatment options for patients with indolent, but generally incurable, lymphomas include a 'watch and wait' approach, single agent alkylators, nucleoside analogues, combination chemotherapy, immunotherapy with monoclonal antibodies, radiolabelled monoclonal antibodies, or interferon (IFN). Vaccine therapy for indolent lymphomas is currently under intense investigation. For aggressive lymphomas, combination chemotherapy remains the standard of care. Major advances in the management of aggressive lymphomas include validation of the international prognostic index and clarification of the role of high-dose therapy with bone marrow or stem cell transplant in patients with relapsed aggressive lymphomas. Multiple randomised pilot trials of high dose therapy as initial therapy for aggressive lymphomas have shown conflicting results and await confirmatory studies.

BACKGROUND Flow cytometric analysis of bone marrow often is used as an adjunct to morphologic evaluation in the staging of patients with non-Hodgkin's lymphoma (NHL). The goal of this study was to define objectively the benefit of flow cytometry in this setting. METHODS The authors reviewed retrospectively all bone marrow specimens submitted between January 1992 and December 1994 to the Washington University Department of Pathology for flow cytometric immunophenotyping to rule out NHL. Results of morphologic examination and flow cytometry were reviewed independently and the ability to detect bone marrow involvement compared. RESULTS Two hundred and seventy-three bone marrow specimens from 190 patients with an established diagnosis of NHL were submitted for flow cytometric analysis at initial presentation, restaging, and/or recurrence. Morphologic evaluation was negative in 69%, positive in 23%, and equivocal in 8%. Flow cytometry was negative in all but 1 morphologically negative bone marrow specimens and 40% of morphologically involved bone marrow specimens. Two of 23 morphologically equivocal bone marrow specimens were positive by flow cytometry. An additional 86 specimens were obtained to rule out NHL in patients without an established diagnosis of NHL. The majority of patients had a history of human immunodeficiency virus infection, cytopenia, or unexplained fevers. Morphologically, one specimen was involved with NHL, 5 were equivocal, and 80 were negative. All specimens were negative by flow cytometry. CONCLUSIONS In this study, flow cytometric analysis improved the detection of NHL in bone marrow in only 3 of 273 samples, 2 of which were suspicious morphologically. Flow cytometry of bone marrow aspirates has a limited role in the routine staging and follow-up of patients with an established diagnosis of NHL. Cancer 1998;82:1154-9. © 1998 American Cancer Society.

The objective of this study was to compare the outcomes of patients with classical Hodgkin lymphoma (cHL) who achieved complete remission with frontline therapy and then underwent either clinical surveillance or routine surveillance imaging.In total, 241 patients who were newly diagnosed with cHL between January 2000 and December 2010 at 3 participating tertiary care centers and achieved complete remission after first-line therapy were retrospectively analyzed. Of these, there were 174 patients in the routine surveillance imaging group and 67 patients in the clinical surveillance group, based on the intended mode of surveillance. In the routine surveillance imaging group, the intended plan of surveillance included computed tomography and/or positron emission tomography scans; whereas, in the clinical surveillance group, the intended plan of surveillance was clinical examination and laboratory studies, and scans were obtained only to evaluate concerning signs or symptoms. Baseline patient characteristics, prognostic features, treatment records, and outcomes were collected. The primary objective was to compare overall survival for patients in both groups. For secondary objectives, we compared the success of second-line therapy and estimated the costs of imaging for each group.After 5 years of follow-up, the overall survival rate was 97% (95% confidence interval, 92%-99%) in the routine surveillance imaging group and 96% (95% confidence interval, 87%-99%) in the clinical surveillance group (P = .41). There were few relapses in each group, and all patients who relapsed in both groups achieved complete remission with second-line therapy. The charges associated with routine surveillance imaging were significantly higher than those for the clinical surveillance strategy, with no apparent clinical benefit.Clinical surveillance was not inferior to routine surveillance imaging in patients with cHL who achieved complete remission with frontline therapy. Routine surveillance imaging was associated with significantly increased estimated imaging charges.

These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

This first study in humans was designed to evaluate the safety and dosimetry of a cellular proliferative marker, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-18F-fluoroethoxy)-5-methylbenzamide (18F-ISO-1), and evaluate the feasibility of imaging tumor proliferation by PET in patients with newly diagnosed malignant neoplasms. Methods: Patients with biopsy-proven lymphoma, breast cancer, or head and neck cancer underwent 18F-ISO-1 PET. Tumor 18F-ISO-1 uptake was assessed semiquantitatively by maximum standardized uptake value, ratios of tumor to normal tissue and tumor to muscle, and relative distribution volume ratio. The PET results were correlated with tumor Ki-67 and mitotic index, from in vitro assays of the tumor tissue. The biodistribution of 18F-ISO-1 and human dosimetry were evaluated. Results: Thirty patients with primary breast cancer (n = 13), head and neck cancer (n = 10), and lymphoma (n = 7) were evaluated. In the entire group, tumor maximum standardized uptake value and tumor-to-muscle ratio correlated significantly with Ki-67 (τ = 0.27, P = 0.04, and τ = 0.38, P = 0.003, respectively), but no significant correlation was observed between Ki-67 and tumor–to–normal-tissue ratio (τ = 0.07, P = 0.56) or distribution volume ratio (τ = 0.26, P = 0.14). On the basis of whole-body PET data, the gallbladder is the dose-limiting organ, with an average radiation dose of 0.091 mGy/MBq. The whole-body and effective doses were 0.012 mGy/MBq and 0.016 mSv/MBq, respectively. No adverse effects of 18F-ISO-1 were encountered. Conclusion: The presence of a significant correlation between 18F-ISO-1 and Ki-67 makes this agent promising for evaluation of the proliferative status of solid tumors. The relatively small absorbed doses to normal organs allow for the safe administration of up to 550 MBq, which is sufficient for PET imaging in clinical trials.

The introduction provides a summary of the Hodgkin lymphoma and non-Hodgkin lymphoma surveillance screening guidelines promulgated by several clinical and governmental organizations throughout the world. Since the term non-Hodgkin lymphoma describes more than 40 histologically discrete diseases associated with wide variations in clinical aggressiveness, a single approach to surveillance based on stage is not appropriate [1]. Similarly, Hodgkin lymphoma can be divided into classical and lymphocyte-predominant subtypes, associated with somewhat more aggressive and indolent behaviors, respectively. To accommodate this clinical heterogeneity, surveillance guidelines are frequently vague, offering a wide range of suggested surveillance tests and testing intervals [2]. It is also important to point out that, for the most part, such guidelines are based upon expert opinion, and adherence to them has not been shown to improve clinical outcomes. Overall, current guidelines for surveillance serve best as a starting point for the discussion of cancer survivorship related to Hodgkin lymphoma and non-Hodgkin lymphoma, and do not represent an evidence-based approach. We hope future studies will allow rigorous evaluation of the clinical value and cost-effectiveness of various surveillance schedules and modalities. Until that time, in our practice we generally favor office visits consisting of clinical history, physical examination, patient education about possible symptoms of relapse, and periodic laboratory testing. We typically recommend radiologic imaging in asymptomatic patients annually for the first 2 years after treatment, or as dictated by symptoms, physical examination, and/or other findings. Such an approach minimizes radiology testing that may be costly, invasive, and anxiety-provoking for the patient.

These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.