{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:53:09Z","timestamp":1790963589981,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T00:00:00Z","timestamp":1677196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"American Society of Clinical Oncology Young Investigator Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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 \u226518 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\u201384). The median number of prior lines of treatment was five (range 1\u20138), including 10 patients (58.8%) who had progressed on prior nivolumab therapy. Most treatment related events were mild (&lt;Grade 3) and expected from the individual side effect profiles of ibrutinib and nivolumab. In the intent to treat population (n = 17), the ORR and CRR were 51.9% (9\/17) and 29.4% (5\/17), which did not meet the prespecified efficacy endpoint of a CRR of 50%. In patients who received prior nivolumab therapy (n = 10), the ORR and CRR were 50.0% (5\/10) and 20.0% (2\/10), respectively. At a median follow up of 8.9 months, the median PFS was 17.3 months, and the median DOR was 20.2 months. There was no statistically significant difference in median PFS between patients who received previous nivolumab therapy versus patients who were nivolumab na\u00efve (13.2 months vs. 22.0 months, p = 0.164). Conclusions: Combined nivolumab and ibrutinib led to a CRR of 29.4% in R\/R cHL. Although this study did not meet its primary efficacy endpoint of a CRR of 50%, likely due to enrollment of heavily pretreated patients including over half of who had progressed on prior nivolumab treatment, responses that were achieved with combination ibrutinib and nivolumab therapy tended to be durable even in the case of prior progression on nivolumab therapy. Larger studies investigating the efficacy of dual BTK inhibitor\/immune checkpoint blockade, particularly in patients who had previously progressed on checkpoint blockade therapy, are warranted.<\/jats:p>","DOI":"10.3390\/cancers15051437","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T01:37:52Z","timestamp":1677202672000},"page":"1437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin\u2019s Lymphoma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8982-6877","authenticated-orcid":false,"given":"Walter","family":"Hanel","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polina","family":"Shindiapina","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bond","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6355-3671","authenticated-orcid":false,"given":"Yazeed","family":"Sawalha","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8216-3457","authenticated-orcid":false,"given":"Narendranath","family":"Epperla","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7603-6454","authenticated-orcid":false,"given":"Timothy","family":"Voorhees","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9477-4581","authenticated-orcid":false,"given":"Rina Li","family":"Welkie","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory K.","family":"Behbehani","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-4568","authenticated-orcid":false,"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wing K.","family":"Chan","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E.","family":"Brammer","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Jaglowski","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6838-2410","authenticated-orcid":false,"given":"John C.","family":"Reneau","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth A.","family":"Christian","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basem M.","family":"William","sequence":"additional","affiliation":[{"name":"Blood and Marrow Transplant and Cell Therapy Program, OhioHealth, 500 Thomas Ln #A3, Columbus, OH 43214, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathon B.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road NE, B4013, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Baiocchi","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kami","family":"Maddocks","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristie A.","family":"Blum","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road NE, B4013, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8870-4162","authenticated-orcid":false,"given":"Lapo","family":"Alinari","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, The Ohio State University, 460 W 10th Ave., Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1182\/hematology.2021000256","article-title":"Double-refractory Hodgkin lymphoma: Tackling relapse after brentuximab vedotin and checkpoint inhibitors","volume":"2021","author":"Epperla","year":"2021","journal-title":"Hematology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1200\/EDBK_238799","article-title":"Relapsed and Refractory Classical Hodgkin Lymphoma: Keeping Pace With Novel Agents and New Options for Salvage 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