Strategic Sequencing in Advanced Mycosis Fungoides: Choosing Between Immunomodulatory, HDAC, and Targeted Therapies

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Advanced mycosis fungoides with nodal involvement presents particular therapeutic challenges, requiring treatment strategies adapted from peripheral T-cell lymphoma (PTCL) management approaches. Standard skin-directed therapies and blood-clearing agents provide limited benefit in this setting, necessitating systemic approaches that effectively penetrate nodal compartments. HDAC inhibitors and pralatrexate represent primary options, with pralatrexate requiring dose modifications specific to CTCL compared to PTCL applications.

Single-agent chemotherapy approaches are preferred for long-term management in visceral disease settings, though chronic use introduces unique toxicity considerations. Gemcitabine, when used continuously for over a year, carries risks of hemolytic uremic syndrome and pulmonary toxicity. Liposomal doxorubicin presents cumulative dose concerns, with unclear safe exposure limits compared to conventional doxorubicin's established 450 mg/m² threshold. These chronic toxicity patterns differ significantly from traditional oncology applications.

CTCL patients typically require 50% dose reductions compared to systemic T-cell lymphoma protocols due to enhanced treatment sensitivity and tolerability issues. This phenomenon may relate to the indolent nature of cutaneous lymphomas and altered tumor cell metabolism. Pralatrexate commonly causes exfoliative dermatitis, creating a "tumor lysis" effect in skin tissue that can be devastating for patients. Careful dose management and toxicity monitoring are essential for maintaining treatment tolerability while achieving therapeutic objectives in this challenging patient population.