In Vitro and In Vivo Radiation Resistance Associated With CD3 Surface Antigen Expression in T-Lineage Acute Lymphoblastic Leukemia

Abstract

AbstractThe radiobiologic features of primary clonogenic blasts (referred to also as T-lineage leukemic progenitor cells) from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia (ALL) patients were analyzed. Intrinsic radiation sensitivity differed substantially among primary clonogenic blasts from 34 newly diagnosed patients. The mean D0 (37% dose slope), SF2 (surviving fraction at 200 cGy), and α values (initial slope of the survival curve) were 141 ± 15 cGy, 0.31 ± 0.04, and 0.630 ± 0.093 Gy–1, respectively. Among newly diagnosed cases, nine had SF2 values of ≥ 0.50 and α values of ≤0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic blasts using the multitarget and linear quadratic models of cell survival. Of these nine radiation resistant cases, seven were CD3+. Furthermore, the mean D0 (162 ± 20.8 cGy) and SF2 (0.377 ± 0.057) values for the 20 CD3+ cases were significantly higher than the D0 (108.6 ± 18.2 cGy) and SF2 (0.204 ± 0.051) values for the 14 CD3– cases (P < .05). Thus, clonogenic blasts from CD3+ newly diagnosed T-lineage ALL patients were more resistant to radiation than clonogenic blasts from CD3– newly diagnosed T-lineage ALL patients. Nineteen T-lineage ALL patients received autologous bone marrow transplants during complete remission. Pretransplant conditioning consisted of total body irradiation (TBI) combined with high-dose chemotherapy. Primary clonogenic blasts from patients who relapsed after bone marrow transplantation (BMT) displayed a particularly high degree of intrinsic radiation resistance with a mean D0 value of 333 cGy and an a value of 0.112 Gy-1. The expression of CD3 antigen appeared to predict the outcome of relapsed T-lineage ALL patients undergoing autologous BMT after TBI plus high-dose chemotherapy. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission after BMT were 60% ± 22% (mean relapse – free interval = 1.6 ± 0.7 years) for CD3– patients and 0% ± 0% (mean relapse – free interval = 0.2 ± 0.0 years) for CD3+ patients (P = .002). Furthermore, the mean percentage of CD3-positive leukemic marrow blasts at presentation or relapse before BMT was significantly lower than the mean percentage of CD3-positive leukemic marrow blasts at relapse after BMT. Notably, in cultured leukemic bone marrow specimens from newly diagnosed as well as relapsed patients, colony blasts surviving in vitro radiation expressed CD3 more vividly than did colony blasts in unirradiated cultures. Thus, the expression of CD3 surface antigen in T-lineage ALL appears to be a harbinger of in vitro as well as in vivo radiation resistance.