Treatment with HDAC inhibitors in ENKTL has an association with EBV reactivation

Kim, S.J. and Kim, W.S. recently responded to the comments of Tan et al. in the Annals of Oncology about their recently published study on Epstein-Barr Virus (EBV) reactivation in Extranodal Natural Killer/T-cell Lymphoma (ENKTL) patients. Their responding commentary included:

  • Supporting their original statement that romidepsin should be avoided in ENKTL patients due to EBV reactivation based upon:
    • Their own phase-II study where romidepsin was a single agent
    • Their in vitro studies showing EBV reactivation in ENKTL cell lines after treatment with three different HDAC inhibitors.
    • Additional studies which have also shown an association between HDAC inhibitors and reactivation of EBV e.g. Tsai et al, and Lee et al.
  • Agreement that in R/R ENKTL, without any other options, a combination of two or more drugs
    • One PR and one CR reported by Tan et al. (2015) in R/R ENKL pts treated with panobinostat and bortezomib in a phase-II study without EBV reactivation
    • Implied HDAC inhibitor + proteasome inhibitor could be possible without EBV reactivation
  • Unclear how proteasome inhibitor reduces the effect of HDAC inhibition on EBV reactivation

In conclusion, Kim and Kim stated that a larger study in R/R ENKTL patients needs to be conducted to better understand whether bortezomib combined with a HDAC inhibitor, such as romidepsin, could be both effective while mitigating the effect on EBV reactivation.

References:
  1. Tan, D. et al. Histone deacetylase (HDAC) inhibitors when combined with a proteasome inhibitor are safe and effective in patients with extranodal natural killer/T-cell lymphoma (ENKTL). Annals of Oncology. 2016 Jun. 27 (9): 1811-1812. doi: 10.1093/annonc/mdw231.
  2. Kim, S.J. and Kim, W.S. Reply to the letter to the editor ‘Epstein–Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin, histone deacetylase (HDAC) inhibitors when combined with a proteasome inhibitor are safe and effective in patients with extranodal natural killer/T-cell lymphoma’. Annals of Oncology. 2016 Nov. 27 (11): 2133-2134. doi: 10.1093/annonc/mdw296.
  3. Tsai, PF. et al. Interplay between PKCδ and Sp1 on Histone Deacetylase Inhibitor-Mediated Epstein-Barr Virus Reactivation. Journal of Virology. 2011 Mar. 85 (5): 2273-2385. doi: 10.1128/JVI.01602-10.
  4. Lee, HH. et al. Essential role of PKCdelta in histone deacetylase inhibitor-induced Epstein-Barr virus reactivation in nasopharyngeal carcinoma cells. Journal of General Virology. 2008 Apr. 89: 878-883. doi: 10.1099/vir.0.83533-0
  5. Tan, D. et al. Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: an open-label, multicentre phase 2 trial. Lancet Haematology. 2015 Aug. 2(8):e326-33. doi: 10.1016/S2352-3026(15)00097-6.