Immunophenotype predicts radiation resistance in T-lineage acute lymphoblastic leukemia and T-lineage non-Hodgkin's lymphoma

Abstract

In the preclinical arm of our study, the radiobiologic features of primary malignant cells from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia/non-Hodgkin's lymphoma patients were analyzed using clonogenic assays. A marked heterogeneity existed relative to the intrinsic radiation sensitivity of clonogenic T-lineage ALL/NHL cells from 42 patients. The mean SF 2 (surviving fraction at 200 cGy) and α values (initial slope of the survival curve) were 0.36 ± 0.04, and 0.558 ± 0.079 Gy −1. Fourteen cases had SF 2 values of ≥ 0.50 and α values of ≤ 0.2 Gy −1, consistent with a marked intrinsic radiation resistance at the level of clonogenic leukemia/lymphoma cells. Of these 14 radiation resistant cases, 12 were CD3 +. Furthermore, the SF 2 and D 0 values of the 28 CD3 + cases were significantly higher than the SF 2 and D 0 values of the 14 CD3 − cases (SF 2: 0.441 ± 0.048 versus 0.189 ± 0.045, p = 0.002; D 0: 189.6 ± 26.3 cGy versus 108.7 ± 18.2 cGy, p = 0.047) and CD3 + cases had smaller α values than CD3 − cases (0.454 ± 0.087 versus 0.765 |+- 0.152, = 0.06). Thus, clonogenic cells from CD3 + T-lineage ALL/NHL patients were more resistant to radiation than clonogenic cells from CD3 − T-lineage ALL/NHL patients. In the clinical arm of our study, 33 T-lineage ALL/NHL patients received autologous bone marrow transplants during remission. Pretransplant conditioning consisted of total body irradiation combined with high dose chemotherapy. The expression of CD3 antigen predicted the outcome of relapsed T-lineage ALL/NHL patients undergoing autologous bone marrow transplantation following total body irradiation plus high dose chemotherapy. Overall, the Kaplan-Meier estimate and standard error of the probability of remaining in remission at 3.5 years was 11 ± 9% with a median relapse-free interval of 102 days. The disease-free survival at 3.5 years was 8 ± 7% with a median disease-free survival time of 96 days. Notably, the expression of CD3 antigen on T-lineage ALL/NHL cells correlated with the probability of relapse after bone marrow transplantation. While 16 of 19 CD3 + patients relapsed after bone marrow transplantation, only 3 of 8 CD3 − patients relapsed. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission at 1 year after bone marrow transplantation were 7 ± 6% (median relapse-free interval = 74 days) for CD3 + patients (n = 19) and 63% 17% for CD3 − patients (n = 8) ( p = 0.006). Two of the 5 CD3 − T-lineage ALL/NHL patients, who did not relapse, remain alive and in remission at 2.3 years and 3.6 years post-bone marrow transplantation, respectively. Taken together, our preclinical and clinical results prompt the hypothesis that CD3 surface antigen expression in T-lineage ALL/NHL is associated with in vitro as well as in vivo radiation resistance.