Dissimilar DNA Damage to Blood Lymphocytes After ¹⁷⁷Lu-Labeled DOTATOC or Prostate-Specific Membrane Antigen Therapy

DNA double-strand breaks in cells of radionuclide-treated patients are quantifiable by immunofluorescence microscopy, using phosphorylation of histone-variant H2AX (γ-H2AX) to mark radiation-induced foci (RIFs). Using this method, we compared excess RIFs side by side in recipients of ¹⁷⁷Lu-DOTATOC or ¹⁷⁷Lu-prostate specific membrane antigen-617 (PSMA) radioligands. We also examined relations between blood dose and dose rate, RIFs, and platelet counts. Methods: Venous blood samples were obtained from 48 patients subjected to ¹⁷⁷Lu-labeled radioligand therapy (¹⁷⁷Lu-DOTATOC, 26; ¹⁷⁷Lu-PSMA, 22) to quantify blood lymphocyte RIFs and blood activity concentrations at various time points, including baseline (before injection) and postinjection readings (5 min, 30 min, 4 h, 24 h, 48 h, and 72 h). Absorbed doses and dose rates to blood were derived from sequentially assessed blood activity concentrations and γ-camera imaging. Platelet levels in routine blood tests were monitored for 3 d after injection to assess responses. Results: RIF counts averaged 0.25 ± 0.15 at baseline. Postinjection RIF counts were significantly higher than baseline values, peaking at 5 min (average, 3.93 ± 2.51 min) and declining thereafter. Compared with RIF counts of ¹⁷⁷Lu-DOTATOC, those of ¹⁷⁷Lu-PSMA were significantly higher at 5 min after injection and significantly lower at 72 h after injection. These differences could not be fully explained by blood doses and dose rates, which were significantly higher for ¹⁷⁷Lu-PSMA than for ¹⁷⁷Lu-DOTATOC treatment at every time point. RIF counts overall correlated with dose rates across all time points (Pearson r = 0.78; P < 0.01) and with absorbed dose until 4 h after injection only (Pearson r = 0.42; P < 0.01). Declines in platelet concentration correlated significantly with RIFs at 72 h after injection (Pearson r = -0.34; P < 0.05). Conclusion: Although values generated by the currently used blood dosimetry model correlated with RIF counts, the difference observed in ¹⁷⁷Lu-DOTATOC and ¹⁷⁷Lu-PSMA treatment groups was unexplained. Significantly more RIFs were found in ¹⁷⁷Lu-DOTATOC recipients by comparison, despite lower dose rates and blood doses, exposing a potential limitation.