Epigenetics in peripheral T-cell lymphoma (PTCL)

Epigenetics is the study of alterations that occur in organisms caused by alterations to gene expression, not by a genetic mutation. Classic examples of epigenetic processes are DNA and histone modification by acetylation/deacetylation and methylation/demethylation. These processes are responsible for the silencing or overexpression of genes, the dysregulation of which can result in the silencing of tumor-suppressor genes and overexpression of proto-oncogenes.

Epigenetic dysregulation is found in many malignancies and has been the subject of targeted drug development studies. However, translating this into clinical practice for the treatment of hematological malignancies has mainly been limited to patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma and T-cell lymphoma (TCL) (1). Lorenzo Falchi presented his work on the use of drugs targeting epigenetic dysregulation in peripheral TCL (PTCL) at the International Conference on Malignant Lymphoma (ICML) in June 2019, Lymphoma hub secretariat interviewed him on this subject). Falchi et al., conducted phase I/II trial of the use of oral 5-azacytidine (AZA; a DNA methyltransferase inhibitor) and romidepsin (ROMI; a histone deacetylase inhibitor) for the treatment of newly diagnosed (ND) or relapsed/refractory (R/R) PTCL. The presentation and published abstract (2), covered the phase II portion of the study.

Study design:

• AZA 300mg daily, for the first 14 days
• ROMI 14mg/ms on days 8, 15, 22 and then every 35 days
• Primary outcome was overall response rate (ORR)
• Other endpoints were progression-free survival (PFS) and duration of response (DOR)
• Next-generation sequencing (NSG) was also performed on pre-treatment tumor samples to determine any correlations between epigenetic gene mutations and response
• 25 patients with a median age of 63 were included and were enrolled consecutively

Key findings:

• Of 25 (11 were ND, 14 were R/R) enrolled patients 19 patients were evaluated for response
  • ORR was 68% (13/19) which included the complete response in 42% (8/19)
  • In ND patients, ORR was 75% and CR was 37%
  • In R/R patients, ORR was 64% and CR 45%
  • Of the 11 evaluable patients with angioimmunoblastic T-cell lymphoma (AITL) or Primary cutaneous follicular helper T-cell lymphoma (PTCL-TFH), the only one didn’t respond, and of the responders, six had CR
• In terms of adverse events (AE);
  • 39% had thrombocytopenia
  • 39% had neutropenia
  • 17% lung infection
  • 13% febrile neutropenia
  • Lower grade toxicities included anemia, diarrhea, fatigue, nausea, and vomiting
  • No patients discontinued therapy due to AE
  • Two deaths, one from a progressive disease, one from unknown causes
• At median follow up of 5.8 months, median DOR has not been reached
• Median PFS:
  • Entire population – 7.9 months
  • ND – 7.9 months
  • R/R – not reached
• NGS of pre-treatment tumor samples has identified a possible association between a TET2 gene mutation and response to treatment
  • Often patients carrying a TET2 mutation, nine responded
  • Only one of the three patients with wild-type TET2 responded

Conclusion

The data from this phase II study demonstrates the potential tolerability and utility of targeting epigenetic dysregulation in PTCL. The AZA-ROMI combination treatment was particularly active in the small proportion of patients with AITL and PTCL-TFH in the trial. Falchi et al., also concluded that that TET2 mutation and PTCL disease subtype may predict response.