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Immunoreconstitution following childhood acute lymphoblastic leukemia (ALL) is a complex process during which various immune functions recover differentially. This process is difficult to elucidate since variables are interrelated and require simultaneous evaluation, rendering conventional statistical methods inappropriate.We used principal components analysis (PCA) and projection of latent structures (PLS) to evaluate immune competence in 32 children treated for ALL. One or 6 months after completion of therapy, the relation between lymphocyte subpopulations, lymphocyte function and response to vaccination with tetanus, diphtheria and hemophilus influenzae, was investigated.PCA demonstrated that increasing treatment intensity correlated with progressive immune dysfunction. Children treated with high intensity had poor response to vaccination associated with loss of humoral memory, decreased CD4+45RA+ T-lymphocytes and increased CD5+ B-lymphocytes. Patients treated with intermediate intensity had better preservation of humoral memory but decreased CD4+45RA+ T-cells. Patients with a low intensity regimen had similar vaccination response and lymphocyte levels as controls.Our findings demonstrate the utility of PCA and PLS in detecting hidden structures in complex data and suggest that, even 6 months after therapy, patients treated with intermediate and high intensity have attenuated responses to de novo antigens whereas those with high intensity also respond poorly to recall antigens. Pediatr Blood Cancer 2011;56:1078–1087. © 2011 Wiley-Liss, Inc.