PT  - JOURNAL ARTICLE
AU  - Shankar Vallabhajosula
AU  - Stanley J. Goldsmith
AU  - Klaus A. Hamacher
AU  - Lale Kostakoglu
AU  - Shota Konishi
AU  - Mathew I. Milowski
AU  - David M. Nanus
AU  - Neil H. Bander
TI  - Prediction of Myelotoxicity Based on Bone Marrow Radiation-Absorbed Dose: Radioimmunotherapy Studies Using <sup>90</sup>Y- and <sup>177</sup>Lu-Labeled J591 Antibodies Specific for Prostate-Specific Membrane Antigen
DP  - 2005 May 01
TA  - Journal of Nuclear Medicine
PG  - 850--858
VI  - 46
IP  - 5
4099  - http://jnm.snmjournals.org/content/46/5/850.short
4100  - http://jnm.snmjournals.org/content/46/5/850.full
SO  - J Nucl Med2005 May 01; 46
AB  - 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) (90Y-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.