Correlation of red marrow radiation dosimetry with myelotoxicity: empirical factors influencing the radiation-induced myelotoxicity of radiolabeled antibodies, fragments and peptides in pre-clinical and clinical settings

Abstract

Usually, the red marrow (RM) is the first dose-limiting organ in systemic radionuclide therapy, e.g., radioimmuno-or radiopeptide therapy. However, several studies have obtained rather poor correlations between the marrow doses and the resulting toxicities. Red marrow doses are mostly not determined directly, but are derived from blood or whole-body doses. The aim of our recent work was to analyze, in a nude mouse model in more detail, additional factors than just total dose, such as dose rate or relative biological effectiveness (RBE) factors, that may influence the resulting myelotoxicity. Furthermore, we wanted to analyze, whether correlations between the red marrow doses and the resulting myelotoxicities can be found in clinical metabolic endo-radiotherapy. The maximum tolerated activities (MTAs) and doses (MTDs) of several murine, chimeric and humanized immunoconjugates as complete IgG or fragments (F(ab)(2), Fab), as well as peptides, labeled with beta(-)- (such as (131)I or (90)Y), Auger electron- (such as (125)I or (111)In), or alpha-emitters (such as (213)Bi) were determined in nude mice. Blood counts were monitored at weekly intervals; bone marrow transplantation (BMT) was performed in order to support the assumption of the RM as dose-limiting. The radiation dosimetry was derived from biodistribution data of the various conjugates, accounting for cross-organ radiation; the activities in the blood, bone, bone marrow, and major organs were determined over time. Dosimetry and myelotoxicity data of three clinical radioimmunotherapy trials, involving a total of 82 colorectal cancer patients, treated with (131)I-labeled anti-CEA IgG, and twelve non-Hodgkin's lymphoma patients, treated with (131)I-labeled anti-CD20 IgG, were analyzed. In the preclinical model, at the respective MTAs, the RM doses differed significantly between the three conjugates: e.g., with (131)I-labeled conjugates, the maximum tolerated activities were#10; 260 microCi for IgG, 1200 microCi for F(ab)(2), and 3 mCi for Fab, corresponding to blood doses of 17 Gy, 9 Gy, and 4 Gy, respectively. However, initial dose rates were 10 times higher with Fab as compared to IgG, and still 3 times higher as compared to F(ab)(2); interestingly, all 3 deliver approximately 4 Gy within the first 24 h. The MTDs of all three conjugates were increased by BMT by approximately 30%. Similar observations were made for the (90)Y-labeled conjugates. Higher blood-based RM doses were tolerated with Auger-emitters than with conventional beta(-)-emitters, whereas the MTDs were similar between alpha- and beta(-)-emitters. In accordance to dose rates never exceeding those occurring at the single injection MTA, re-injections of (131)I-, (90)Y-, or (213)Bi-labeled Fab' were tolerated without increased lethality, if administered 24-48 h apart, whereas reinjection of bivalent conjugates was not possible. Clinically, a sigmoidally shaped dose-effect correlation was found in colorectal cancer patients treated with (131)I-anti-CEA IgG. Previous mitomycin chemotherapy was identified as additional myelosensitizing factor leading to enhanced myelotoxicity. At comparable doses, non-Hodgkin's lymphoma patients developed higher degrees of myelotoxicity with a less clearly pronounced predictability from red marrow doses. In summary, results in the murine model suggest a strong influence of the dose rate (or better: dose per unit time), not only total dose on the resulting myelotoxicity, whereas the influence of high- (alpha, Auger/conversion electrons) versus low-LET (beta,gamma) type radiation seems to be much lower than expected from previous in vitro data. The lower myelotoxicity of Auger e(-) emitters is probably due to the short path length of their low-energy electrons, which cannot reach the nuclear DNA if the antibody is not internalized into the stem cells of the red marrow. Clinically, additional factors than just marrow dose (e.g., previous myelotoxic therapy, bone marrow involvement by metastatic malignancy) seem to a, bone marrow involvement by metastatic malignancy) seem to affect the resulting myelotoxicity.