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Results from a phase I trial of pembrolizumab plus vorinostat in relapsed/refractory B-cell non-Hodgkin lymphoma.

Authors
  • Godfrey, James1
  • Mei, Matthew1
  • Chen, Lu2
  • Song, Joo Y3
  • Bedell, Victoria3
  • Budde, Elizabeth1
  • Armenian, Saro4
  • Puverel, Sandrine1
  • Nikolaenko, Liana1
  • Chen, Robert1
  • Daniels, Shari1
  • Kennedy, Neena1
  • Peters, Lacolle1
  • Rosen, Steven T1
  • Forman, Stephen J1
  • Popplewell, Leslie L1
  • Kwak, Larry W1
  • Herrera, Alex F5
  • 1 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA.
  • 2 Department of Information Sciences, City of Hope, Duarte, CA.
  • 3 Department of Pathology, City of Hope, Duarte, CA.
  • 4 Department of Pediatrics, City of Hope, Duarte, CA.
  • 5 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA. [email protected].
Type
Published Article
Journal
Haematologica
Publisher
Ferrata Storti Foundation
Publication Date
Feb 01, 2024
Volume
109
Issue
2
Pages
533–542
Identifiers
DOI: 10.3324/haematol.2023.283002
PMID: 37470137
Source
Medline
Language
English
License
Unknown

Abstract

Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors exhibit favorable immunomodulatory effects and demonstrate synergistic anti-tumor immune responses with anti-PD-1 therapy in preclinical models. We, therefore, developed a phase I study to evaluate the safety and preliminary efficacy of pembrolizumab with vorinostat in relapsed/refractory B-cell lymphomas. Patients were treated in a dose-escalation cohort using a Rolling 6 design followed by an expansion cohort at the recommended phase II dose (R2PD). Fifty-two patients were enrolled (32 Hodgkin and 20 non-Hodgkin lymphoma [NHL]). Here, we report safety data from the dose escalation cohort, and the toxicity and efficacy within NHL patients. Vorinostat was administered twice daily on days 1-5 and 8-12 (dose-level [DL]1: 100 mg; DL2: 200 mg) and pembrolizumab (200 mg) was administered on day 1 of each 3-week cycle. Of six patients treated at DL1, one had a dose-limiting toxicity (DLT) (Stevens-Johnson syndrome [SJS]), and one of six had a DLT at DL2 (thromboembolism); therefore, DL2 was the RP2D. The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. The most common adverse events were hypertension, diarrhea, and cytopenias. Of 20 NHL patients, nine had follicular lymphoma (FL) and 11 had diffuse large B-cell lymphoma (DLBCL). Five DLBCL patients had primary mediastinal B-cell lymphoma (PMBL). The complete and overall response rates (CR and ORR) were 11% and 22% for FL and 45% and 55% for all DLBCL. Amongst DLBCL, the CR and ORR was 80% and 80% for PMBL and 17% and 33% for non-PMBL. In conclusion, pembrolizumab with vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL (clinicaltrials gov. Identifier: NCT03150329).

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