USE OF THE LINEAR-QUADRATIC MODEL TO COMPARE DOSES DELIVERED TO THE BONE-MARROW BY I-131 LYM-1 RADIOIMMUNOTHERAPY

The purpose of this study was to use the linear-quadratic model to det ermine biologically effective doses (BED) that were delivered to the b one marrow by multiple infusions of radiolabeled antibodies. Granulocy topenia and thrombocytopenia are the dose-limiting toxicities of radio immunotherapy. If the linear-quadratic model can be applied to radioim munotherapy in a manner such that BED correlate with peripheral blood counts, then one will have a theoretical means for developing new frac tionation schedules, possibly leading to an improvement in the therape utic index of radioimmunotherapy. Twenty-nine patients with B-cell non -Hodgkin's lymphomas that had progressed despite intensive chemotherap y but who lacked a significant number of malignant cells in their bone marrow were treated with multiple 18-100 mCi/m(2) intravenous infusio ns of Lym-1, a murine monoclonal antibody that binds to a tumor-associ ated antigen, labeled with I-131. Peripheral blood counts were measure d in order to assess bone marrow toxicity. BED were calculated using t he formula: BED = d(1 + gd/(alpha/beta)) - 0.693(T-n-T-k)/alpha T-p, w here d represents the absorbed dose of radiation delivered to the bone marrow by each I-131-Lym-1 infusion (which was estimated from the cum ulated radioactivity in both the blood and the whole body), alpha is t he 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 blood count nadir after an I-131-Lym-1 infusion, T-k is the time at w hich bone marrow proliferation begins after the start of treatment, T- p is the doubling time of the bone marrow after the blood count nadir has been reached and g is a factor that depends on the duration of irr adiation relative to the repair half-life of human bone marrow. The bi ologically effective dose delivered to the bone marrow by each I-131-L ym-1 infusion was calculated; BED delivered by multiple I-131-Lym-1 in fusions were added together in order to arrive at a total BED for each patient. The following assumptions were made: the binding of I-131-Ly m-1 to normal B-cells in the bone marrow did not significantly contrib ute to the absorbed dose of radiation, the bone marrow received a homo geneous absorbed dose, the rate of clearance of I-131-Lym-1 from the b ody was independent of the amount of I-131-Lym-1 present, the repair h alf-time = 0.5 hours, alpha = 0.9 Gy(-1) and alpha/beta = 10 Gy for ea rly effects. T-k was estimated to be 3 days. When there was a clearly defined nadir in the platelet counts between I-131-Lym-1 infusions, T- n equaled 24+/-2 days (mean+/-SE) and T-p equaled 27+/-5 days (mean+/- SE; similar values were observed for the leukocyte and granulocyte cou nts). BED ranged from 0-2.6 Gy(10). The decrease in leukocyte, granulo cyte and platelet counts in response to I-131-Lym-1 therapy correlated moderately well with increasing BED delivered to the bone marrow when 30-60 mCi infusions of I-131-Lym-1 were administered (the correlation coefficients ranged from -0.55 to -0.67). For unclear reasons, when 4 0-100 mCi/m(2) infusions of I-131-Lym-1 were administered, there was a weaker association between leukocyte, granulocyte and platelet counts and BED (the correlation coefficients ranged from 0 to -0.08). As exp ected, there was no clear association between erythrocyte counts and B ED, regardless of the radioactivity administered (the correlation coef ficients were -0.19 and 0.06 for 30-60 mCi and 40-100 mCi/m(2) infusio ns, respectively). The association between leukocyte, granulocyte and platelet counts and BED may have been weakened by variable bone marrow reserve at the start of treatment, the binding of I-131-Lym-1 to norm al B-cells in the bone marrow and/or the delivery of heterogeneous abs orbed doses of radiation to the bone marrow. Future work will address bone marrow dosimetry in patients with known disease at this site.