Smart Start: Rituximab, Lenalidomide, and Ibrutinib Alone and in Combination with Standard Chemotherapy for Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma: Final Phase II Results

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

Smart start: Final results of rituximab, lenalidomide, and ibrutinib lead in prior to combination with chemotherapy for patients with newly diagnosed diffuse large B-cell lymphoma.

7508 Background: The non-germinal center (non-GCB) subtype of Diffuse Large B-cell Lymphoma (DLBCL) is associated with inferior outcomes from standard immuno-chemotherapy. The BTK inhibitor ibrutinib (I) and immunomodulatory agent lenalidomide (L) have promising activity in non-GCB DLBCL as single agents, and result in synthetic lethality in non-GCB DLBCL models when combined. In relapsed non-GCB DLBCL, rituximab (R), L and I result in overall response rate (ORR) of 55% (Ramchandren, ASH 2018). We report the final results of RLI prior to chemotherapy in newly diagnosed non-GCB DLBCL patients, an investigator initiated, single-arm, open-label, phase 2 study. Methods: Adult patients with non-GCB DLBCL, determined by the Hans method, with adequate organ function and performance status were eligible. The primary objectives were to determine (1A) the ORR of two cycles of RLI as initial therapy, and (1B) the complete response rate (CRR) after 6 cycles of chemotherapy combined with RLI. All patients were treated with rituximab 375 mg/m2 IV day 1, ibrutinib 560 mg po daily, and lenalidomide 25 mg po days 1-10 of 21 day cycles for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy. Results: The protocol accrued 60 patients from May 2016 – February 2019, with 52 patients evaluable for disease response (2 withdrew consent prior to restaging, 6 pending restaging prior to abstract deadline). The median age was 64 years (range: 30-83), 28% were ≥ 70 years, and 50% were female. Half the patients had poor risk IPI, 61% had advanced stage, and 71% had a Ki-67 of ≥ 80%. One patient had a fatal fungal infection (CNS aspergillosis) attributed to high dose corticosteroids and RLI, leading to prohibition of corticosteroids during the RLI only cycles with no further fungal infections identified. The ORR for 2 cycles of RLI was 84.6% (n=44), and the CRR was 38.5% (n=20). One patient refused to proceed with the pre-planned chemotherapy after achieving a CR with 2 cycles of RLI, and remains relapse free 18 months later. Conclusions: The Smart Start trial demonstrates the chemotherapy-free combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25 mg is highly effective in patients with newly diagnosed non-GCB DLBCL. Additional studies evaluating more cycles of RLI with less chemotherapy consolidation are planned. Clinical trial information: NCT02636322.

Freeze-thaw risk in solid masonry: are moisture reference years able to represent real climate conditions?

Today, there is no consensus on the selection method of representative exterior boundary conditions when performing HAM (Heat Air Moisture) simulations on building envelopes. Many existing methods to select moisture reference years (MRY) fail to provide an acceptable validation in terms of quantified risk assessment. Although new methods have been suggested during the past few years, the influence of several parameters on the selection of “critical years” in long-term datasets still needs to be assessed. The objective of this paper is to validate the application of MRY’s to evaluate freeze-thaw risk in retrofitted solid masonry. Furthermore, the influence of the chosen wall assembly, damage criterion, preconditioning and start date of the evaluation period on the ranking of critical years is assessed, using a 31-year meteorological dataset of Brussels. Results indicate that for a given wall assembly and freeze-thaw criterion, as well as a smart start date of the evaluated period, single year simulations entail a similar ranking of critical years as the corresponding year in the 31-year simulation. The number of critical freeze-thaw cycles only varies between 0 - 2 cycles (0 - 2.9%). However, changing the wall assembly and damage criterion, alters the top 5 ranking of critical years substantially.

Entrepreneurial Ecosystems

Regional development is founded on creative and dynamic territories, where several partners collaborate to create ideal conditions to improve life living, business, job creation and regional competitiveness. Smart cities use networks to promote economic and political efficiency and to allow social, cultural and urban development. These regions present high standards respecting some indicators associated with, innovation, creativity, environment, life quality, entrepreneurial activities and support facilities. Entrepreneurial ecosystems are an important dimension for a region or city to become smart. These entrepreneurial ecosystems emerge as a compromise to foster entrepreneurship and economic development in a regional context. This chapter has two folds. Firstly, it aims to the discussion of core concepts, such as, smart city and how to define an entrepreneurial ecosystem. It also aims to its features, to understand if an entrepreneurial ecosystem is born or made and it pretends to show an example of a smart start-up city, which is the case of Lisbon.

Entrepreneurial Ecosystems

Regional development is founded on creative and dynamic territories, where several partners collaborate to create ideal conditions to improve life living, business, job creation and regional competitiveness. Smart cities use networks to promote economic and political efficiency and to allow social, cultural and urban development. These regions present high standards respecting some indicators associated with, innovation, creativity, environment, life quality, entrepreneurial activities and support facilities. Entrepreneurial ecosystems are an important dimension for a region or city to become smart. These entrepreneurial ecosystems emerge as a compromise to foster entrepreneurship and economic development in a regional context. This chapter has two folds. Firstly, it aims to the discussion of core concepts, such as, smart city and how to define an entrepreneurial ecosystem. It also aims to its features, to understand if an entrepreneurial ecosystem is born or made and it pretends to show an example of a smart start-up city, which is the case of Lisbon.