RADIATION-RESISTANCE OF PRIMARY CLONOGENIC BLASTS FROM CHILDREN WITH ACUTE LYMPHOBLASTIC-LEUKEMIA

Purpose: Detailed comparative analyses of the radiation sensitivity of primary clonogenic blasts from children with acute lymphoblastic leuk emia (ALL) were performed to achieve a better understanding of clinica l radiation resistance in ALL. Methods and Materials: The radiation se nsitivity of primary clonogenic blasts from 74 children with newly dia gnosed acute lymphoblastic leukemia (ALL) was analyzed using leukemic progenitor cell (LPC) assays. Primary bone marrow blasts from all 74 p atients were exposed to ionizing radiation and subsequently assayed fo r LPC-derived blast colony formation. Radiation survival curves of pri mary clonogenic blasts (i.e., LPC) were constructed for each of the ne wly diagnosed patients using computer programs for the single-hit mult itarget as well as the linear quadratic models of cell survival. Resul ts: A marked interpatient variation in intrinsic radiation sensitivity was observed between LPC populations. The SF2 values ranged from 0.01 to 1.00 (median: 0.36; mean +/- SE = 0.40 +/- 0.03), and the alpha va lues ranged from 0.00 Gy(-1) to 3.27 Gy(-1) (median: 0.280 Gy(-1); mea n +/- SE = 0.43 +/- 0.09 Gy(-1)). Patients were divided into groups ac cording to their sex, age, WBC at diagnosis, cell cycle distribution o f leukemic blasts, and immunophenotype. Only immunophenotype provided a significant correlation with the intrinsic radiation sensitivity of LPC. Patients with B-lineage ALL had higher SF2 (0.47 +/- 0.04 vs. 0.3 1 +/- 0.05, p < 0.05) and smaller a values (0.43 +/- 0.09 Gy(-1) vs. 0 .65 +/- 0.10 Gy(-1), p < 0.05) than T-lineage ALL patients, consistent with greater intrinsic radiation resistance at the level of LPC. Nota bly, 43% of B-lineage ALL cases, but only 27% of T-lineage ALL cases h ad LPC with SF2 greater than or equal to 0.5. Similarly, 66% of B-line age ALL cases, but only 37% of T-lineage ALL cases had LPC with alpha values less than or equal to 0.4 Gy(-1). Combining the two indicators of radiation resistance, we found that only 34% of the B-lineage ALL p atients had none of the two parameters in the respective critical regi ons (alpha less than or equal to 0.4 Gy(-1); SF2 greater than or equal to 0.5), while 63% of the T-lineage patients had none (p < 0.05). In multivariate analyses, the immunophenotypic B-lineage affiliation was the only significant predictor of radiation resistance at the level of LPC. Whether alone or in combination, none of the other variables exa mined, including sex, age, WBC, in vitro plating efficiency, S-phase i ndex, and proliferation index were significantly correlated with the r adiation sensitivity or resistance of LPC. Conclusion: These results o ffer unprecedented evidence for an association between composite immun ophenotype (viz., B-lineage ALL vs T-lineage ALL) and radiation resist ance that may form a basis for modifying radiation conditioning regime ns.