Relative biological effectiveness (RBE) of the alpha-particle emitter 213Bi vs 90Y for hematologic toxicity and efficacy in patients with leukemia

Abstract

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Objectives: RBE is defined as the absorbed dose required to achieve a given biological end-point for a radiation of interest divided by the absorbed dose required for a reference radiation to achieve the same biological end-point. Dose-response studies for nadir duration and percent reduction in leukemic blasts obtained from two separate phase I trials of anti-CD33 antibody, HuM195, radiolabeled with 90Y or, the alpha-particle emitter, 213Bi, previously demonstrated an RBE ≈ 1 (Sgouros '00). The original dose estimates did not account for the effect of cellularity on the absorbed dose to blasts and to normal hematopoietic cells. The objective of this work is to account for cellularity in absorbed dose estimation.

Methods: Cellularity may be defined as the percent marrow volume that is occupied by target cells. In this work, cellularity-dependent electron and alpha-particle absorbed fractions for trabecular active marrow self-dose (Watchman et al. ‘05 and Shah et al. ’05) are used to estimate patient-specific, cellularity-dependent average absorbed doses to leukemic blasts and to normal marrow. The total cellularity, obtained from bone marrow biopsies or aspirates, was multiplied by the pre-therapy %blasts to give the target cell cellularity; one minus this was taken as the normal marrow cellularity. These cellularity estimates were used to obtain the appropriate absorbed fractions for Bi-213/Po-213 alpha-particle emissions or S-factor for Y-90 beta emissions.

Results: Accounting for energy loss due to cellularity reduced the absorbed dose estimates to less than one-half of their original values. The RBE for toxicity (taken as nadir duration) did not change since the dose-response data for 213Bi and 90Y continued to overlap. The RBE for efficacy, as measured by reduction in marrow blasts and given by the separation in the dose-response plots was approximately 2 to 3.

Conclusions: These results highlight the potential importance of using absorbed fractions that reflect patient cellularity in estimating red marrow absorbed dose and also provide a preliminary estimation of RBE in humans for the chosen end-points and reference radiation.