Cardiac NK/T-Cell Lymphoma: Largest Case Series and MYC Inhibition–Radiation Synergy as a Potential Bridge to Modified SMILE

Introduction/Background/Significance: Cardiac involvement by extranodal NK/T-cell lymphoma (ENKTL) is exceedingly rare and almost uniformly fatal, largely because diagnosis is delayed and intensive chemotherapy cannot be delivered promptly. MYC over-expression—common in aggressive or leukemic ENKTL—may represent an actionable radiosensitizing target.

Materials and Methods/Case Presentation/Objective: We retrospectively reviewed three biopsy-proven cases of cardiac ENKTL (largest series to date) and performed a systematic literature review (1960–2025). Two high-MYC leukemic ENKTL patient-derived xenograft (PDX) models were established. Ex-vivo studies compared a small-molecule MYC inhibitor (MYCi-975) ± fractionated irradiation (2 × 2 Gy) against individual SMILE components. Endpoints included viability (CellTiter-Glo), apoptosis (Annexin V/PI), clonogenic survival, and Bliss synergy.

Results/Description/Main Outcome Measures: Median overall survival in our series was 9 days (range 6–36); all patients died before systemic therapy could start. Literature review (n = 19) confirmed 89 % mortality within 30 days. Both PDX lines displayed ≥4-fold higher MYC than non-leukemic ENKTL controls. MYCi-975 monotherapy yielded IC₅₀ ≈ 0.5 μM, inducing >50 % apoptosis at 24 h and >90 % at 72 h. Combining MYCi-975 with 2 × 2 Gy irradiation produced supra-additive cytotoxicity (Bliss excess = 0.23) and >95 % reduction in clonogenic survival versus either treatment alone. RNA-seq showed suppression of pro-proliferative and pro-survival autophagy pathways. No added toxicity was observed in normal PBMCs.

Conclusions: Cardiac ENKTL is rapidly lethal, but MYC inhibition markedly radiosensitizes high-MYC ENKTL models. These findings support a pragmatic bridge strategy—MYCi-975 plus low-dose radiation during critical illness, followed by modified SMILE if the patient stabilizes. Prospective evaluation of MYC-targeted radiosensitization in disseminated ENKTL is urgently warranted.