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Simple Summary: Relapsed or refractory classical Hodgkin lymphoma remains a difficult treatment challenge. Despite responses with the checkpoint inhibitors nivolumab and pembrolizumab, patients eventually progress. Combining other treatments with checkpoint inhibitors may provide more frequent and durable responses in this setting. We conducted a phase II study in relapsed or refractory Hodgkin lymphoma combining nivolumab with the Bruton's tyrosine kinase inhibitor ibrutinib. Although we did not find an increase in the response rate of this combination compared to that previously reported, responses tended to be durable even in patients who progressed on nivolumab therapy prior to enrollment. Larger studies combining Bruton's tyrosine kinase inhibitors with checkpoint blockade are warranted, especially in patients who had progressed previously on checkpoint inhibitor therapy. Background: Relapsed or refractory classical Hodgkin lymphoma (cHL) remains a difficult treatment challenge. Although checkpoint inhibitors (CPI) have provided clinical benefit for these patients, responses are generally not durable, and progression eventually occurs. Discovering combination therapies which maximize the immune response of CPI therapy may overcome this limitation. We hypothesized that adding ibrutinib to nivolumab will lead to deeper and more durable responses in cHL by promoting a more favorable immune microenvironment leading to enhanced T-cell-mediated anti-lymphoma responses. Methods: We conducted a single arm, phase II clinical trial testing the efficacy of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who had received at least one prior line of therapy. Prior treatment with CPIs was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for up to 16 cycles. The primary objective was complete response rate (CRR) assessed per Lugano criteria. Secondary objectives included overall response rate (ORR), safety, progression free survival (PFS), and duration of response (DoR). Results: A total of 17 patients from two academic centers were enrolled. The median age of all patients was 40 (range 20–84). The median number of prior lines of treatment was five (range 1–8), including 10 patients (58.8%) who had progressed on prior nivolumab therapy. Most treatment related events were mild (

Simple Summary: In this study, we present a workflow to understand the modulator of ibrutinib resistance in ABC diffuse large B cell lymphoma by integrating Metabolomics and Gene expression profiling as shown in the graphical abstract. We performed an untargeted metabolomics analysis using a Q-Exactive high-resolution mass spectrometer to dissect the metabolic reprogramming associated with acquired ibrutinib resistance in paired ibrutinib-sensitive and ibrutinib-resistant DLBCL cell lines. Further, we identified common denominators, integrating metabolome and transcriptome data, confirming clinical significance, integrating pathways, and identifying the candidate gene driving ibrutinib resistance and metabolic reprogramming. Our work demonstrates that a multi-omics approach can be a robust and impartial strategy to uncover genes and pathways that cause metabolic deregulation in cancer cells. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton's tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure resulting in the drug-tolerant form. The drug-tolerant clones proliferate faster, have increased metabolic activity, and shift to oxidative phosphorylation; however, how this metabolic programming occurs in the drug-resistant tumor is poorly understood. In this study, we explored for the first time the metabolic regulators of ibrutinib-resistant activated B-cell (ABC) DLBCL using a multi-omics analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomic (gene expression analysis). Overlay of the unbiased statistical analyses, genetic perturbation, and pharmaceutical inhibition was further used to identify the key players contributing to the metabolic reprogramming of the drug-resistant clone. Gene-metabolite integration revealed interleukin four induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in producing various amino acids. We showed for the first time that drug-resistant clones undergo metabolic reprogramming towards oxidative phosphorylation and are modulated via the BTK-PI3K-AKT-IL4I1 axis. Our report shows how these cells become dependent on PI3K/AKT signaling for survival after acquiring ibrutinib resistance and shift to sustained oxidative phosphorylation; additionally, we outline the compensatory pathway that might regulate this metabolic reprogramming in the drug-resistant cells. These findings from our unbiased analyses highlight the role of metabolic reprogramming during drug resistance development. Our work demonstrates that a multi-omics approach can be a robust and impartial strategy to uncover genes and pathways that drive metabolic deregulation in cancer cells. [ABSTRACT FROM AUTHOR]