Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-002097 on 19 February 2021. Downloaded from Use of pembrolizumab with or without pomalidomide in HIV- associated non- Hodgkin’s lymphoma 1 1 1 1 Kathryn Lurain , Ramya Ramaswami, Ralph Mangusan, Anaida Widell, Irene Ekwede,1 Jomy George,2 Richard Ambinder,3 Martin Cheever,4 5 1 6 James L Gulley , Priscila H Goncalves, Hao- Wei Wang, 1,7 1 Thomas S Uldrick , Robert Yarchoan To cite: Lurain K, ABSTRACT INTRODUCTION Ramaswami R, Mangusan R, Background Non- Hodgkin’s lymphoma (NHL) is With current combination antiretroviral et al. Use of pembrolizumab currently the most common malignancy among people therapy (ART), the most common cancer with or without pomalidomide in living with HIV (PLWH) in the USA. NHL in PLWH is more HIV- associated among people living with HIV (PLWH) in the frequently associated with oncogenic viruses than NHL in 1 non- Hodgkin’s lymphoma. USA is non-Hodgkin's lymphoma (NHL). immunocompetent individuals and is generally associated Journal for ImmunoTherapy There is an 11- fold to 17- fold increased life- of Cancer 2021;9:e002097. with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less time risk of NHL in PLWH compared with doi:10.1136/jitc-2020-002097 + immunosuppressive than chemotherapy may decrease the general population, due in part to CD4 T cell lymphopenia but also to immune ► Additional material is infection risk, improve immune control of oncogenic published online only. To view, viruses, and ultimately allow for better lymphoma control. dysregulation, B cell activation, and immune please visit the journal online Methods We conducted a retrospective study of exhaustion from chronic viral antigen stimu- (http:// dx. doi. org/ 10. 1136/ jitc- patients with HIV- associated lymphomas treated with lation.2 3 Similar to the general population, 2020- 002097). pembrolizumab±pomalidomide in the HIV and AIDS diffuse large B cell lymphoma (DLBCL) is Malignancy Branch, Center for Cancer Research, National the most common subtype, but there are also Accepted 13 January 2021 Cancer Institute. rare subtypes that occur almost exclusively in Results We identified 10 patients with stage IV relapsed and/or primary refractory HIV-associa ted NHL PLWH, such as primary effusion lymphoma who were treated with pembrolizumab, an immune (PEL) and plasmablastic lymphoma (PBL). In checkpoint inihibitor, with or without pomalidomide. Five PLWH, DLBCL and PBL are frequently asso- patients had primary effusion lymphoma (PEL): one had ciated with Epstein- Barr virus (EBV). Kaposi http://jitc.bmj.com/ germinal center B cell- like (GCB) diffuse large B cell sarcoma herpesvirus (KSHV, also known as lymphoma (DLBCL); two had non-GCB DLBCL; one had human herpesvirus 8) is the etiologic agent aggressive B cell lymphoma, not otherwise specified; of PEL, with EBV coinfection also present and one had plasmablastic lymphoma. Six patients in the vast majority of cases.4 Several factors received pembrolizumab alone at 200 mg intravenously are believed to contribute to the increased every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg risk of virus- associated NHL in PLWH. HIV- on September 28, 2021 by guest. Protected copyright. orally every day for days 1–21 of a 28- day cycle; and associated immunosuppression causes a loss one sequentially received pembrolizumab alone and of virus- specific T cells allowing decreased then pomalidomide alone. The response rate was 50% control of EBV- infected or KSHV- infected B with particular benefit in gammaherpesvirus-associa ted cell, increasing B cell activation and the risk tumors. The progression-free survival was 4.1 months of malignant B cell transformation.5 Both (95% CI: 1.3 to 12.4) and overall survival was 14.7 months EBV and KSHV are able to evade immune (95% CI: 2.96 to not reached). Three patients with PEL had detection and maintain infection in host leptomeningeal disease: one had a complete response © Author(s) (or their B cells through downregulation of expres- and the other two had long-term disease control. There employer(s)) 2021. Re- use sion of immune surface markers, which are permitted under CC BY-NC. No were four immune-rela ted adverse events (irAEs), all commercial re- use. See rights CTCAEv5 grade 2–3; three of the four patients were able essential for T cell and natural killer (NK) and permissions. Published by to continue receiving pembrolizumab. No irAEs occurred in cell immune surveillance, and this process BMJ. patients receiving the combination of pembrolizumab and may work in tandem with HIV- induced For numbered affiliations see pomalidomide. immunosuppression.6 end of article. Conclusions Treatment of HIV-associa ted NHL with PD-1 inhibitors, such as pembrolizumab pembrolizumab with or without pomalidomide elicited Correspondence to and nivolumab, have proven effective in responses in several subtypes of HIV-associa ted NHL. This Dr Kathryn Lurain; many cancer subtypes, particularly those with approach is worth further study in PLWH and NHL. 7 kathryn. lurain@ nih. gov neoantigens from a high mutational burden. Lurain K, et al. J Immunother Cancer 2021;9:e002097. doi:10.1136/jitc-2020-002097 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-002097 on 19 February 2021. Downloaded from Checkpoint inhibitors are potentially attractive agents addition of pomalidomide, and in this manuscript, we in PLWH as they do not cause further immunosuppres- review our experience with this salvage therapy for HIV- sion, unlike traditional cytotoxic chemotherapies and associated NHL. radiotherapy, and also because of the increase in PD-1- expressing exhausted T cells seen in PLWH compared with the general population.8 While these agents have had relatively disappointing results so far as single agents PATIENTS AND METHODS in aggressive NHL in the immunocompetent population, Study design and patient selection EBV- encoded and/or KSHV- encoded foreign antigens We conducted a retrospective study of all identified patients in HIV- associated NHL may render these tumors poten- with HIV- associated lymphomas treated with pembroli- tially more susceptible to such therapy.9 10 Recent clinical zumab±pomalidomide in the HIV and AIDS Malignancy trials have provided evidence that these agents are safe in Branch, Center for Cancer Research, National Cancer PLWH and have anti- tumor activity in a subset of cases.11 12 Institute (NCI). All patients were participating in one Pomalidomide is a third generation analog of thalid- or more clinical studies (NCT00006518, NCT00092222, omide with immunomodulatory, antiangiogenic, and NCT01419561) and one clinical trial (NCT02595866). antineoplastic properties. Thalidomide and its analogs all All cases were pathologically confirmed in the Labora- work by binding to and modulating the activity of cere- tory of Pathology, NCI, and evaluated at the time of active blon. Pomalidomide is approved by the United States disease. Diagnoses were based on cytopathology and/or Food and Drug Administration (FDA) for the treatment H&E staining of tissue supported by immunohistochem- of multiple myeloma and Kaposi sarcoma, and has been istry. Leptomeningeal involvement of NHL was deter- proven to be safe in PLWH.13 Pomalidomide also has mined by cytopathology and/or flow cytometry of the known activity in certain types of NHL.14 There may be cerebrospinal fluid (CSF), and patients with CSF involve- direct anti- lymphoma activity in part via downregula- ment were followed serially with cytopathology and flow tion of IRF4/MUM1 expression, which is common in cytometry. KSHV tumor status was confirmed by staining HIV- associated NHL.15 16 Pomalidomide can enhance T for latency- associated nuclear antigen (anti-ORF73 rat and NK cell activation, and there is also evidence that it mAB, Advanced Biotechnologies, Eldersburg, Maryland, may render EBV- infected or KSHV- infected tumor cells USA). EBV tumor status was evaluated by in situ hybrid- visible to the immune system by reversing EBV-induced ization against EBV- encoded small RNA. Clinical records and KSHV- induced downregulation of immune surface were reviewed for baseline clinical laboratory parameters markers, such as MHC-1, ICAM-1, and CD86.17 18 Another prior to initiation of therapy. NHL staging and response clinically relevant aspect of pomalidomide is its ability to to treatment were determined according to the Lugano penetrate the central nervous system (CNS), as leptome- classification for NHL, and restaging was performed ningeal involvement is more frequent in HIV- associated every three cycles or more frequently if progressive 23 NHL.14 19 disease was suspected. Disease stabilization of leptome- The standard treatment for NHL after progression on ningeal disease was defined by the lack of new neurologic http://jitc.bmj.com/ or after front- line chemotherapy is second- line combina- symptoms or MRI findings that could be attributed to + + tion chemotherapy, often containing a platinum agent, disease. HIV viral loads and CD4 and CD8 T cell counts followed by autologous hematopoietic stem cell trans- were generally measured every 3 months unless there was plant.20 21 This approach does not generally differ for clinical indication to measure more frequently. Immune- HIV- associated NHL; however, a second-line approach related adverse events (irAEs) were graded according to that spares not only T cells,