Safety and Activity of Lenalidomide in Combination With Obinutuzumab in Patients With Relapsed Indolent Non-Hodgkin Lymphoma: A Single Group, Open-Label, Phase 1/2 Trial

BACKGROUND: Rituximab and lenalidomide is a preferred option for relapsed indolent B cell non-Hodgkin lymphoma. Obinutuzumab may be a superior combination partner with lenalidomide given enhanced antibody dependent cellular cytotoxicity and phagocytosis compared to rituximab. Our aim was to determine the recommended phase 2 dose, safety, and activity of lenalidomide in combination with fixed dose of obinutuzumab in relapsed and refractory indolent B cell non-Hodgkin lymphoma. METHODS: In this single-arm, open-label, phase 1/2 trial, we enrolled patients with relapsed or refractory WHO Grade 1-3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma and adequate performance status (ECOG 0-2) at the MD Anderson Cancer Center. We excluded patients with evidence of ongoing transformation to aggressive lymphoma. During phase 1, 1000 mg intravenous obinutuzumab was administered with three predefined levels of oral lenalidomide in a 3 + 3 dose escalation design to establish lenalidomide 20 mg as the recommended phase 2 dose. During phase 2, patients received induction therapy with six 28-day cycles of lenalidomide 20 mg with intravenous obinutuzumab 1000 mg. In accordance with our prior experience with lenalidomide plus rituximab, patients who were responding to the combination could receive up to 6 additional cycles (up to 12 cycles in total) of combination therapy. Dosing of obinutuzumab was continued in all responding patients after cycle 6 every 2 months for a total of 30 months from the start of therapy. The decision of number of cycles of combination therapy beyond 6 was at discretion of the investigator and was included to allow individualisation of therapy to maximise response while minimising exposure. The co-primary objectives were to evaluate the safety and overall response, defined as the proportion of patients who achieved a complete or partial response in relapsed and refractory indolent non-Hodgkin lymphoma at the end of induction therapy, according to Cheson and colleagues (2007 criteria). The secondary endpoints were complete response after induction therapy and time to event endpoints including time to progression, progression free survival, and overall survival. Analyses were intent to treat in the efficacy cohort and per-treated in the safety population in all patients who received at least one dose of either investigational agent. This trial is registered with ClinicalTrials.gov, NCT01995669. FINDINGS: Between June 03, 2014, and 07 March 2019, we completed planned enrolment, and 66 patients started therapy including 9 patients in phase 1 and 57 patients in phase 2. All patients were evaluated for safety and the 60 patients treated at the recommended phase 2 dose of lenalidomide 20 mg were evaluable for activity. Grade 3-4 haematological toxicities included neutropenia 21% (14/66) and thrombocytopenia 11% (7/66) with no cases of febrile neutropenia. Grade 3-4 non-haematological toxicities included lung infection 8% (5/66), fatigue 8% (5/66) and rash 6% (4/66). By Cheson 2007 criteria, 90% (54/60, 95% CI: 79-96) achieved an overall response at the end of induction meeting the prespecified activity endpoint. Complete responses were seen in 33% (20/60, 95% CI: 22-47) at the end of induction. Median progression free survival, time to progression and overall survival have not been reached after median follow-up of 41.7 months. Estimated 4-year progression free survival rates were 55% (95% CI: 42-73), time to progression of 56% (95% CI: 43-74) and overall survival of 84% (95% CI: 74-95). INTERPRETATION: Our findings suggest that oral lenalidomide with obinutuzumab is safe and highly active in patients with relapsed and refractory indolent B cell non-Hodgkin lymphoma and is associated with prolonged remission duration. The study is limited by the lack of a control arm leading to cross-trial comparisons to evaluate activity. Future randomised trials comparing this regime to rituximab and lenalidomide are warranted. FUNDING: Genentech and an MD Anderson Core grant

Recognition of Plant Leaf Diseases Using CNN

Agriculture improvement is a global economic issue and ongoing challenge in this covid-19 pandemic that is highly dependent on effectiveness. The recognition of the diseases in plant leaf performs a major role in the agriculture industry and city-side greenhouse farms approximate analysis of the leaf disease this article intends to integrate image processing techniques with the “convolutional neural network”, which is one of the deep learning approaches, to classify and detect plant leaf disease and publicly available plant the late data to help treat the leaf as early as possible, which controls the economic loss. This paper has a set that was used which consists of 10 classes of disease and three classes of a plant leaf, this research offers an effective method for detecting different diseases in plant leaf variations. The model was created to detect and recognize healthy plant kinds, such as tomato and potato, and pepper these three leaves will perform under the algorithm called a convolutional neural network. By modifying the parameters and changing the pulling combination, models that have been used to train and test these types of leaf sample images can be created. leaf disease recognition was based on these 10 different types of classes in three different species tomato, potato, and pepper the classification of sample images has reached diseases identification accuracy.</jats:p

Periodicity, complementarity and complexity of 2-adic FCSR combiner generators

Feedback-with-carry shift registers (FCSRs) are nonlinear analogues of linear feedback shift registers (LFSRs). Like the LFSRs, FCSRs are easy to implement and are important primitives in stream cipher design and pseudorandom number generation. In this paper, we investigate the properties of combiner generators that use two 2-adic feedback-with-carry shift registers as primitives. The combining function is simply the XOR function. This choice is motivated by an observation of Arnault and Berger on the high nonlinearity of the FCSR and that of Siegenthaler on the tradeoff between resilience and correlation immunity of boolean functions. When the two FCSRs have odd prime power connection integers with 2 as a primitive root, we determine the exact period of the output sequence. We also prove that if the prime factors of the connection integers of the two FCSRs belong to different equivalence classes modulo 4, then the output sequence is symmetrically complementary. We use this fact to derive upper bounds on the linear complexity and the 2-adic complexity of the output sequence of the FCSR-combiner

An Efficient and Convenient Approach to Synthesis of Tetrahydrobenzo[ b

An efficient and convenient approach to the synthesis of 2-amino-3-cyano-4-aryl-7,7-dimethyl-5-oxo-4H-5, 6, 7, 8- tetrahydro benzo[b]pyran derivatives using tetrabutylammonium bromide (TBABr) as the catalyst is described. This method provides several advantages such as neutral conditions, high yields and simple work procedure