BackgroundThe Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin’s lymphoma population, primarily consisting of patients with DLBCL.MethodsPatients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells.ResultsThirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance.ConclusionsAZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.Trial registrationRegistered at ClinicalTrials.gov: NCT01563302. First submitted 2/13/2012.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0436-5) contains supplementary material, which is available to authorized users.

Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow-up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty-one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co-existing with TP53). Ibrutinib-refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib-refractory MCL.

Blastoid and pleomorphic mantle cell lymphomas (MCLs) are variants of aggressive histology MCL (AH-MCL). AH-MCL can arise de novo (AH-DN) or transform from prior classic variant MCL (AH-t). This study is the first integrated analysis of clinical and genomic characteristics of AH-MCL. Patient characteristics were collected from diagnosis (AH-DN) and at transformation (AH-t). Survival after initial diagnosis (AH-DN) and after transformation (AH-t) was calculated. Regression tree analysis was performed to evaluate prognostic variables and in univariate and multivariate analyses for survival. Whole-exome sequencing was performed in evaluable biopsy specimens. We identified 183 patients with AH-MCL (108 were AH-DN, and 75 were AH-t; 152 were blastoid, and 31 were pleomorphic). Median survival was 33 months (48 and 14 months for AH-DN and AH-t, respectively; P = .001). Factors associated with inferior survival were age (≥72 years), AH-t category, Ki-67 ≥50% and poor performance status. AH-t had a significantly higher degree of aneuploidy compared with AH-DN. Transformed MCL patients exhibited KMT2B mutations. AH-MCL patients with Ki-67 ≥50% had exclusive mutations in CCND1, NOTCH1, TP53, SPEN, SMARCA4, RANBP2, KMT2C, NOTCH2, NOTCH3, and NSD2 compared with low Ki-67 (<50%). AH-t patients have poor outcomes and distinct genomic profile. This is the first study to report that AH-MCL patients with high Ki-67 (≥50%) exhibit a distinct mutation profile and very poor survival.

Background: Diffuse Large B-cell Lymphoma (DLBCL), the most common lymphoid cancer, is classified by the cell of origin into the germinal and non-germinal center (non-GCB) subtypes. The non-GCB subtype is associated with inferior outcomes with standard therapies, but the BTK inhibitor ibrutinib (I) and immunomodulatory agent lenalidomide (L) have moderate activity as single agents and result in synthetic lethality when combined in non-GCB DLBCL models (Yang, Cancer Cell 2012). When added to chemotherapy for DLBCL as single agents, neither I nor L have significantly improved outcomes over chemotherapy alone as they only result in synthetic lethality with each other. In relapsed non-GCB DLBCL, a phase Ib trial of rituximab (R), L and I resulted in an overall response rate (ORR) of 65% and median duration of response of 15.9 months (Goy, Blood 2019). Both I and L are also immunomodulatory, shifting from a tumor-mediated immune anergy to an anti-tumor immune response. Methods: We conducted an investigator initiated, open-label, single-arm phase 2 study (Smart Start, NCT02636322) of RLI alone in a 2 cycle lead in followed by RLI combined with standard chemotherapy for 6 cycles in newly diagnosed non-GCB DLBCL patients. Patients were eligible if they had newly diagnosed non-GCB DLBCL (Hans method), adequate organ function and performance status, and were aged 18y or greater. The primary objectives were 1A: to determine the ORR of 2 cycles of RLI, and 1B: to determine the complete response rate (CRR) after RLI-chemotherapy (CHOP or dose adjusted EPOCH per treating MD choice). Therapy consisted of R 375 mg/m2 IV day 1, ibrutinib 560 mg oral daily, and lenalidomide 25 mg oral days 1-10 of a 21 day cycle for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy. All patients were required to receive growth factor support, and prophylaxis for venous thromboembolism and pneumocystis. Responses were determined with PET/CT as per the Lugano criteria. Results: The protocol accrued 60 patients from May 2016 - February 2019, with 58 patients evaluable for disease response (2 withdrew consent prior to restaging). The median age was 63.5 years (range: 29-83), 28% were >= 70 years, and 50% were female. 51.7% had poor risk R-IPI, 65% had advanced stage, 77% had a Ki-67 of >= 80%, and 54% of patients with available tissue were "double expressor" (DE, MYC and BCL2 overexpression via IHC). The median time from diagnosis to therapy was 24 days. The chemotherapy received was CHOP in 43%, (n=25), dose adjusted EPOCH in 55% (n = 32), and none in 2% (n=1). Over 90% of planned ibrutinib and lenalidomide was able to be administered. 13 patients received less than 6 cycles of chemotherapy (C0 = 1, C4 = 4, C5 = 8) due to toxicity, treating physician preference, or patient refusal. Adverse events were generally similar to what is expected with chemotherapy, with the exception of rash in 32% (9% grade 3) and CNS aspergillosis (n = 1). 2 patients suffered grade 5 events (CNS aspergillosis, clostridium difficile colitis). The ORR for 2 cycles of RLI alone was 86% (n=50), the CRR was 36% (n=21), and patients achieving a PR had an 81% median tumor reduction from baseline. The end of therapy ORR is 100% (CR: 95%, PR 5%), with none of the PR patients having relapsed to date without further therapy. The median follow-up at abstract submission is 16 months (1 - 33.5m), with 1 year PFS estimate of 92.5% and OS estimate of 96.5%. Response and survival were not different based upon chemotherapy selected, baseline clinical or pathological variables including DE status or Ki-67%, or number of cycles of therapy received. Correlative studies, including circulating tumor DNA assessment at baseline, after 2 cycles of RLI, and at the end of therapy and beyond are ongoing and will be presented at the meeting. Conclusions: The Smart Start trial demonstrates the combination of rituximab 375 mg/m2 IV, ibrutinib 560 mg oral daily, and lenalidomide 25mg oral d1-10 prior to and with chemotherapy results in impressive response rates and survival in newly diagnosed non-GCB DLBCL compared with historical outcomes. Established adverse prognostic variables including non-GCB, high Ki-67%, and double expression of MYC and BCL2 had similar outcomes with other patients with RLI-based therapy. Further studies are planned to expand the lead-in phase with more targeted agents and number of cycles, and to administer fewer cycles of chemotherapy for patients achieving a CR with a targeted therapy lead-in. Figure Disclosures Westin: Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; MorphoSys: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Genentech, Inc.: Honoraria, Research Funding. Oki:Jazz: Employment. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chuang:Sage Evidence-based Medicine & Practice Institute: Consultancy. Neelapu:Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Cellectis: Research Funding; Karus: Research Funding; Novartis: Consultancy; Merck: Consultancy, Research Funding; Acerta: Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Allogene: Consultancy; Incyte: Consultancy; Poseida: Research Funding; Pfizer: Consultancy. OffLabel Disclosure: Ibrutinib and lenalidomide are not yet indicated for DLBCL, we will describe our trial

Introduction. Cytokine release syndrome (CRS) and neurotoxicity (NT)(also known as immune effector cell-associated neurotoxicity syndrome or ICANS) are commonly observed after chimeric antigen receptor (CAR) T-cell therapy. While the clinical features of CRS have been extensively described, limited data exists for NT. Here, we report clinical and radiological features of NT after standard of care (SOC) axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Methods. Pts with r/r LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 and 04/2019 were included in the study. All pts received anti-seizure prophylaxis with levetiracetam starting on the day of axi-cel infusion for 30 days. CRS and NT were prospectively graded according to CARTOX criteria (Neelapu et al, Nat Rev Clin Oncol, 2018). Association between continuous variables were assessed using the bivariate Pearson correlation. Results. Ninety-five pts were included in the study, 72 (76%) with diffuse LBCL, 17 (18%) with transformed follicular lymphoma, and 6 (6%) with primary mediastinal LBCL. Median age was 60 (range, 18-85), 71 (75%) were male. Median number of previous therapies was 4 (range, 2-15), 26 (27%) had a previous autologous stem cell transplant (SCT), and 1 (1%) a previous allogeneic SCT. Eight (8%) pts had prior central nervous system lymphomatous involvement (parenchymal in 5), and 39 (41%) had prior neurological and/or psychiatric medical history. After axi-cel infusion, NT of any grade was observed in 65 (68%) pts, grade ³3 in 46 (48%)(Table). No significant association was observed between above outlined baseline characteristics and development of NT. Median time from axi-cel infusion to NT onset was 5 days (range, 0-25 days) and median duration was 6 days (range, 1-52 days); no new onset/recurrent NT was observed beyond day 30. Among the 65 pts who developed NT, a CT head without contrast was performed in 48, and was not evaluable in 2 because of motion artifacts. Among the 46 evaluable scans, 1 (4%) was abnormal as compared to baseline, and showed new onset cortical edema (non-diffuse but symmetrical). An MRI brain with contrast was performed in 36 pts, but was not evaluable in 10 because of lack of baseline, motion artifacts or differences in imaging sequences. Among the 26 evaluable scans, 15 (58%) showed abnormal findings, including autoimmune encephalitis-like, characterized by symmetric white matter changes of the pons and hippocampus (6; Fig. A), stroke-like (4; Fig. B), LMD-like (3; Fig. C) and PRES-like (2; Fig. D), with concomitant cortical edema in 5. EEGs were performed in 52 pts (>1/pt, for a total of 116 EEGs) and were abnormal in 47 (90%). Focal and/or diffuse slowing was the most common abnormality (isolated finding in 35 [73%] pts), while epileptiform discharges and/or non-convulsive status epilepticus (NCSE) were observed 12 (27%) pts. A lumbar puncture was performed in 12 pts: median white blood cell count was 2 cells/µL (range, 0-6), median protein 47 mg/dL (range, 13-600), median glucose 69 mg/dL (range, 30-111), and cytology was positive for malignant cells in 2 (7%) pts. Convulsive seizure was observed in 4 (6%) pts and 10 (15%) received additional anti-seizure therapy for convulsive or non-convulsive seizures. Among the 65 pts with NT, dexamethasone up to 20 mg IV Q6H was given to 42 (65%) pts, methylprednisolone 1000 mg IV daily to 12 (18%), and tocilizumab to 64 (98%; during CRS or CRS with concurrent NT). Overall, 93 (98%) pts developed CRS, grade >3 in 27 (28%). A significantly higher rate of NT of any grade (96% vs 57%, p<0.001) or grade >3 (81% vs 35%, p<0.001) was observed among pts with grade >3 CRS. After a median follow-up of 4 months, 6-month progression-free (PFS) and overall survival (OS) rates were 60% and 65%, respectively. Significantly shorter 6-month PFS (46% vs 80%, p=0.02) and OS rates (56% vs 83%, p=0.01) were observed among pts developing NT of any grade. Conclusions. Our results suggest that multiple radiological patterns of NT after axi-cel are possible in r/r LBCL pts, MRI being more sensitive than CT scan for their detection. NCSE is a common event, supporting the use of seizure prophylaxis and EEGs for evaluation of these pts. Pts with NT experience a worse outcome, and additional clinical and biological predictors of NT will be analyzed and presented at the meeting. Figure Disclosures Nastoupil: Spectrum: Honoraria; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria. Westin:47 Inc: Research Funding; Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Pinnix:Merck: Research Funding. Hawkins:Novartis Pharmaceuticals: Other: advisory panels. Neelapu:Precision Biosciences: Consultancy; Novartis: Consultancy; Allogene: Consultancy; Incyte: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy. Chi:Kite, A Gilead Company: Consultancy, Honoraria, Other: Kite Patient Management Advisory Board.