APPLICATION OF THE LINEAR-QUADRATIC MODEL TO MYELOTOXICITY ASSOCIATEDWITH RADIOIMMUNOTHERAPY

The purposes of this study were: (1) to use the linear-quadratic model to determine time-dependent biologically effective doses (BEDs) that were delivered to the bone marrow by multiple infusions of radiolabele d antibodies, and (2) to determine whether granulocyte and platelet co unts correlate better with BED than administered radioactivity, which does not take stem cell repopulation, i.e., time, into consideration. Twenty patients with B-cell malignancies that had progressed despite i ntensive chemotherapy and who had a significant number of malignant ce lls in their bone marrow were treated with multiple 0.7-3.7 GBq/m(2) ( 18-100 mCi/m(2)) intravenous infusions of Lym-1, a murine monoclonal a ntibody that binds to a tumour-associated antigen, labeled with iodine -131. Granulocyte and platelet counts were measured in order to assess bone marrow toxicity. BEDs were calculated according to the formula: BED=D(1+gD/(alpha/beta))-0.693(T-n-T-k)/alpha T-p, where D represents the absorbed dose of radiation delivered to the red marrow by penetrat ing emissions of I-131 throughout the whole body and nonpenetrating em issions of I-131 in the blood and bone marrow, alpha is a factor that depends on the duration of irradiation relative to the repair half-lif e of human bone marrow, cc is the coefficient of nonrepairable damage per Gy, beta is the coefficient of repairable damage per Gy(2), T-n is the time required to reach the granulocyte or platelet count nadir af ter an I-131-Lym-1 infusion, T-k is the time at which bone marrow prol iferation begins after the start of treatment and T-p is the doubling time of the bone marrow after the granulocyte or platelet count nadir has been reached. The cumulative I-131-Lym-1 radioactivity administere d to each patient was calculated. Biologically effective doses from mu ltiple I-131-Lym-1 infusions were summated in order to arrive at a tot al BED for each patient. There was a weak association between granuloc yte and platelet counts and radioactivity (the correlation coefficient s were -0.23 and -0.60, respectively). Likewise, there was a weak asso ciation between granulocyte and platelet counts and BED (the correlati on coefficients were -0.27 and -0.30, respectively). The attempt to ta ke bone marrow absorbed doses and overall treatment time into consider ation with the linear-quadratic model did not produce a stronger assoc iation than was observed between peripheral blood counts and administe red radioactivity, The association between granulocyte and platelet co unts and BED may have been weakened by several factors, including vari able bone marrow reserve at the start of I-131-Lym-1 therapy and the d elivery of heterogeneous absorbed doses of radiation to the bone marro w.