Caspase 2 and caspase 3 as predictors of complete remission and survival in adults with acute lymphoblastic leukemia

Dysregulation of apoptosis is an important mechanism in leukemogenesis. Cas pases are cysteine proteases that play a major role in the activation of ap optotic pathways and chemotherapy-induced cell death, High levels of inacti ve, uncleaved caspase 2 and caspase 3 have recently been associated,vith po or survival in patients with acute myelogenous leukemia, We hypothesized a similarly significant role for caspase 2 and caspase 3 in patients with acu te lymphoblastic leukemia. We determined levels of uncleaved caspase 2 and caspase 3 by quantitative Western blot analysis in peripheral blood samples of 45 adults with newly diagnosed ALL, We evaluated patient prognostic var iables and caspase levels using multivariate logistic and Cox regression mo dels to determine their impact on complete remission rate and overall survi val probability, Levels of caspase 2 and, to a lesser degree, caspase 3 wer e highly associated with cytogenetic abnormalities, with lower levers in th e diploid group (P = 0.016 and P = 0.10, respectively). No association betw een either caspase level and the percentage of bone marrow blasts was found . A high level of caspase 3 (>0.37 as determined graphically) was significa ntly associated with achieving complete remission (CR; P = 0.006), A multiv ariate logistic regression analysis including age, WBC count, percentage of peripheral and marrow blasts, hemoglobin, albumin, lactate dehydrognase, b ilirubin, and creatinine determined that a high level of caspase 3 was the most significant predictor of CR (P = 0.025, adjusted), with albumin the on ly other significant variable (P = 0.031), Caspase 2 levels were not associ ated with probability of CR, In a multivariate Cox model for survival, howe ver, levels of caspase 2 above 0.37 were associated with a lower survival p robability than were levels below that threshold (P = 0.064), High levels o f caspase 3 may have a significant effect on achieving CR, Because of the l imited power (n = 45) of our study, the significance of caspase 2 and caspa se 3 on overall survival remains to be validated by further investigations.