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930 Nivolumab (Anti-PD1) Therapy for Relapsed/ Refractory Primary Central Nervous System Lymphoma and Primary Testicular Lymphoma

Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Retrospective/Observational Studies
Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Retrospective/Observational Studies: CNS Lymphomas and Treatment Related Complications
Monday, December 5, 2016: 4:00 PM
Room 30 (San Diego Convention Center)

Lakshmi Nayak, MD1, Fabio Iwamoto, MD2*, Ann S. LaCasce, MD3, Srinivasan Mukundan Jr.4*, Margaretha G M Roemer5*, Bjoern Chapuy, MD PhD5, Philippe Armand, MD, PhD3,6, Scott J. Rodig7 and Margaret A. Shipp, MD1

1Dana-Farber Cancer Institute, Boston, MA
2Columbia University, New York, NY
3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
4Brigham and Women's Hospital, Boston, MA
5Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
6Division of Hematology, Dana-Farber Cancer Institute, Boston, MA
7Dana Farber, Boston, MA

Background: Primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare and aggressive extranodal non-Hodgkin lymphomas with shared molecular features and a poor prognosis. PCNSL is currently treated with high-dose methotrexate (HD-MTX) based induction chemotherapy. Younger patients who are healthy and eligible for consolidation treatment are considered for whole brain radiation (WBRT) or high-dose chemotherapy with autologous stem-cell transplant (ASCT). Despite this, nearly 50% of patients with PCNSL relapse within 2 years of diagnosis and one third of patients have primary refractory disease. PTL is treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). However, almost 50% of patients with PTL progress after induction treatment, frequently with CNS or contralateral testicular involvement. Treatment options are limited for patients with recurrent and refractory PCNSL or PTL, and the majority of patients ultimately die of their disease.

We recently identified frequent 9p24.1/ PD-L1(CD274)/ PD-L2 (PDCD1LG2) copy number alterations and additional translocations in PCNSL and PTL (Chapuy and Roemer et al Blood 2016; 127:869-81). These genetic alterations are associated with increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. Activation of PD-1 signaling by PD-L1 or PD-L2 binding leads to a reversible state of T-cell “exhaustion” characterized by decreased T-cell receptor signaling, reduced T-cell proliferation and survival, perturbed metabolism and altered transcription factor expression. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations such as classical Hodgkin’s lymphoma prompted us to test the efficacy of this approach in PCNSL and PTL.

Patients and Methods: We treated 5 patients with recurrent/refractory PCNSL and PTL with off-label Nivolumab, a humanized IgG4 monoclonal antibody checkpoint inhibitor that targets PD-1 and blocks binding by PD-L1 or PD-L2. Median age was 64 (range, 54-85) years with a median Karnofsky Performance Score (KPS) of 70 (40-80) %. Four patients had multiply recurrent disease (3 patients with PCNSL and 1 patient with PTL and CNS relapse); 1 patient had primary refractory PCNSL. All patients had been treated with standard of care treatments and had no other available options. Prior therapies included HD-MTX based chemotherapy, pemetrexed, high-dose cytarabine, WBRT and thiotepa-based chemotherapy followed by ASCT. All patients signed informed consent and were treated with nivolumab at 3mg/kg intravenously every 2 weeks. Only 1 patient received corticosteroids (dexamethasone 2mg daily) during initial nivolumab treatment; steroids were rapidly tapered and discontinued in 4 weeks. Additionally, 1 patient received 3 doses of rituximab and 2 others received WBRT.

All patients had objective radiographic responses to treatment with nivolumab, including 4 complete responses and 1 partial response. The patient with CNS relapse from PTL had complete radiographic resolution of CNS abnormalities with persistent intraocular disease that required vitrectomy. All responses were confirmed at repeat restaging. The median number of nivolumab treatments to objective radiographic response was 3 (range, 2-4). The 4 patients who were symptomatic at the initiation of nivolumab therapy had complete or near-complete resolution of neurologic signs/symptoms and a marked improvement in KPS. All patients are alive and remain progression-free at this time. Four patients continue to receive treatment. The median progression-free survival is 9 (range, 7-11) months.

Conclusion: Our pilot series indicates that nivolumab is active in primary refractory and relapsed/refractory PCNSL and PTL with CNS relapse. Based on our preclinical molecular data and these pilot clinical results, a multi-institutional phase 2 open-label, single-arm trial of nivolumab in recurrent and refractory PCNSL and PTL patients (CA209-647) is scheduled to open shortly.

Disclosures: LaCasce: Forty Seven: Consultancy; Seattle Genetics: Consultancy. Armand: Tensha: Research Funding; Otsuka: Research Funding; Sigma Tau: Research Funding; Sequenta: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Roche: Research Funding; Infinity: Consultancy; BMS: Consultancy, Research Funding. Shipp: Bayer: Research Funding; Bayer: Research Funding; Cell Signaling: Honoraria; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Signaling: Honoraria; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Bristol-Myers Squibb: Consultancy, Research Funding.

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