title: Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial.
abstract: BACKGROUND
  Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma.
  
  
  METHODS
  We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m(2) intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722.
  
  
  RESULTS
  We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15.4 months (IQR 10.1-21.0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%).
  
  
  CONCLUSIONS
  The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma.
  
  
  BACKGROUND
  National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jason R
authors: JR
authors: Westin
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Fuliang
authors: F
authors: Chu
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Min
authors: M
authors: Zhang
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Luis E
authors: LE
authors: Fayad
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Larry W
authors: LW
authors: Kwak
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Nathan
authors: N
authors: Fowler
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jorge
authors: J
authors: Romaguera
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Fredrick
authors: F
authors: Hagemeister
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Michelle
authors: M
authors: Fanale
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Felipe
authors: F
authors: Samaniego
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Lei
authors: L
authors: Feng
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Veerabhadran
authors: V
authors: Baladandayuthapani
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Zhiqiang
authors: Z
authors: Wang
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Wencai
authors: W
authors: Ma
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Yanli
authors: Y
authors: Gao
authors: Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Michael
authors: M
authors: Wallace
authors: Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Luis M
authors: LM
authors: Vence
authors: Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Laszlo
authors: L
authors: Radvanyi
authors: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Tariq
authors: T
authors: Muzzafar
authors: Cure Tech, Yavne, Israel.
authors: Rinat
authors: R
authors: Rotem-Yehudar
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: R Eric
authors: RE
authors: Davis
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: sneelapu@mdanderson.org.
authors: Sattva S
authors: SS
authors: Neelapu
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D012008:Recurrence; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D061026:Programmed Cell Death 1 Receptor; D000069283:Rituximab; C585832:pidilizumab