Cross-resistance of Belinostat and Romidepsin in Non–T Follicular Helper Peripheral T-cell Lymphoma Models Suggests Subtype-Specific Implications for Belinostat-CHOP

The phase III study of romidepsin plus CHOP for peripheral T-cell lymphoma (PTCL) yielded negative results in the overall analysis and showed that outcomes were only improved in the T follicular helper (TFH) subgroup of PTCL, with no benefit in non-TFH PTCL. Belinostat, another histone deacetylase (HDAC) inhibitor, is now the primary candidate to test whether HDAC inhibition can improve treatment outcomes in first-line PTCL. Whether belinostat shares romidepsin's TFH-specific clinical activity remains uncertain, and therefore whether it is better to include or exclude non-TFH subtypes may be a crucial choice for a forthcoming confirmatory trial of belinostat-CHOP in first-line PTCL. We evaluated whether these agents are cross-resistant in non-TFH lymphomas by conducting in vitro drug sensitivity profiling with belinostat, romidepsin, and other pairs of mechanistically related agents in 30 non-TFH human T- and NK-cell lymphoma cultures. Sensitivities to romidepsin and belinostat were strongly correlated (ρ = 0.77, P < 10-6) and comparable with correlations observed for other same-mechanism drug pairs (e.g., doxorubicin/etoposide) and significantly higher than for drug pairs without mechanistic similarity. These findings indicate substantial cross-resistance between romidepsin and belinostat in non-TFH PTCL. If belinostat shares romidepsin's subtype-specific activity, a first-line trial of belinostat plus CHOP with broad patient enrollment may risk diluting benefit in TFH lymphomas by including non-TFH cases, whereas a TFH-focused design could maximize the likelihood of the trial's success.