Toxoplasmosis-associated hemophagocytic lymphohistiocytosis during tumor-infiltrating lymphocyte therapy.

BACKGROUND

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome triggered by infections, malignancies, or autoimmune disorders. Tumor-infiltrating lymphocyte (TIL) therapy requires lymphodepleting chemotherapy and interleukin-2, producing profound immunosuppression. While HLH-like syndromes have been characterized after chimeric antigen receptor T-cell therapy, HLH has not been reported in the setting of TIL therapy. Toxoplasma gondii is a recognized but uncommon parasitic trigger of secondary HLH.

CASE SUMMARY: A 68-year-old male with metastatic melanoma undergoing TIL therapy presented with altered mental status. He had chronic lymphopenia and reported gastrointestinal intolerance to trimethoprim-sulfamethoxazole, documented as a sulfonamide allergy without formal testing, limiting prophylaxis to inhaled pentamidine, which has no anti-Toxoplasma activity. On admission, he was febrile (39.3°C) with pancytopenia, hypofibrinogenemia (44 mg/dL [normal 200-400]), hyperferritinemia (>30,000 ng/mL [normal 30-300]), hypertriglyceridemia (410 mg/dL [normal 150]), and elevated soluble CD25 (6,979.4 pg/mL [normal 175.3-858.2]); HScore was 283 (>99% probability of HLH). Bone marrow biopsy revealed bradyzoites, tachyzoites, pseudocysts, and hemophagocytosis. Disseminated toxoplasmosis was confirmed by positive serum Toxoplasma IgG, negative IgM, and cerebrospinal fluid Toxoplasma PCR of 13,700 copies/mL (reference: not detected), with brain MRI demonstrating targetoid enhancing lesions. Treatment with pyrimethamine, sulfadiazine, and leucovorin was initiated, but the patient continued to deteriorate and transitioned to comfort measures.

CONCLUSION

This represents the first toxoplasmosis-associated HLH during TIL therapy. It underscores the importance of distinguishing drug intolerance from true allergy, ensuring Toxoplasma-active prophylaxis in profoundly immunosuppressed patients, and recognizing that HIV-derived CD4 thresholds may not apply to non-HIV immunocompromised populations.