Prediction of myelotoxicity based on bone marrow radiation-absorbed dose: Radioimmunotherapy studies using ⁹⁰Y- and ¹⁷⁷Lu-labeled J591 antibodies specific for prostate-specific membrane antigen

In radioimmunotherapy, myelotoxicity due to bone marrow radiation-absorbed dose is the predominant factor and frequently is the dose-limiting factor that determines the maximum tolerated dose (MTD). With ⁹⁰Y- and ¹³¹I-labeled monoclonal antibodies, it has been reported that myelotoxicity cannot be predicted on the basis of the amount of radioactive dose administered or the bone marrow radiation-absorbed dose (BMrad), estimated using blood radioactivity concentration. As part of a phase I dose-escalation study in patients with prostate cancer with ⁹⁰Y-DOTA-J591 (DOTA = 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid)(³⁰Y-J591) and ¹⁷⁷Lu-DOTA-J591 (¹⁷⁷Lu- J591), we evaluated the potential value of several factors in predicting myelotoxicity. Methods: Seven groups of patients (n = 28) received 370-2,775 MBq/m² (10-75 mCi/m²) of ¹⁷⁷Lu-J591 and 5 groups of patients (n = 27) received 185-740 MBq (5-20 mCi/m²) of ⁹⁰Y-J591. Pharmacokinetics and imaging studies were performed for 1-2 wk after ¹⁷⁷Lu treatment, whereas patients receiving ⁹⁰Y had these studies performed with ¹¹¹In-DOTA-J591 ( ¹¹¹In-J591) as a surrogate. The BMrad was estimated based on blood radioactivity concentration. Myelotoxicity consisting of thrombocytopenia or neutropenia was graded 1-4 based on criteria of the National Cancer Institute. Results: Blood pharmacokinetics are similar for both tracers. The radiation dose (mGy/MBq) to the bone marrow was 3 times higher with ⁹⁰Y (0.91 ± 0.43) compared with that with ¹⁷⁷Lu (0.32 ± 0.10). The MTD was 647.5 MBq/m² with ⁹⁰Y-J591 and 2,590 MBq/m² with ¹⁷⁷Lu-J591. The percentage of patients with myelotoxicity (grade 3-4) increased with increasing doses of ⁹⁰Y (r = 0.91) or ¹⁷⁷Lu (r = 0.92). There was a better correlation between the radioactive dose administered and the BMrad with ¹⁷⁷Lu (r = 0.91) compared with that with ⁹⁰Y (r = 0.75). In addition, with ¹⁷⁷Lu, the fractional decrease in platelets (FDP) correlates well with both the radioactive dose administered (r = 0.88) and the BMrad (r = 0.86). In contrast, with ⁹⁰Y, there was poor correlation between the FDP and the radioactive dose administered (r = 0.20) or the BMrad (r = 0.26). Similar results were also observed with white blood cell toxicity. Conclusion: In patients with prostate cancer, myelotoxicity after treatment with ¹⁷⁷Lu-J591 can be predicted on the basis of the amount of radioactive dose administered or the BMrad. The lack of correlation between myelotoxicity and ⁹⁰Y-J591 BMrad may be due to several factors. ⁹⁰Y-J591 may be less stable in vivo and, as a result, higher amounts of free ⁹⁰Y may be localized in the bone. In addition, the cross-fire effect of high-energy β-particles within the bone and the marrow may deliver radiation dose nonuniformly within the marrow.