P53 MUTATIONS ARE ASSOCIATED WITH RESISTANCE TO CHEMOTHERAPY AND SHORT SURVIVAL IN HEMATOLOGIC MALIGNANCIES

We analyzed the prognostic value of p53 mutations for response to chem otherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations wer e detected by single-stranded conformation polymorphism (SSCP) analysi s of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing . A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS , and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated ca ses and 66 of 81 (81%) nonmutated cases treated with intensive chemoth erapy achieved complete remission (CR) (P =.005) and none of five muta ted cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial surv ival was 2.5 months in mutated cases, and 15 months in nonmutated case s (P < 10(-5)). In the MDS patients who received chemotherapy (intensi ve chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P =.004), and median a ctuarial survival was 2.5 and 13.5 months, respectively (P < 10(-5)). In all MDS cases (treated and untreated), the survival difference betw een mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambuc il and/or CHOP and/or fludarabine) responded, as compared with 29 of 3 6 (80%) nonmutated cases (P=.02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < 10(-5)). In 35 of t he 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our f indings show that p53 mutations are a strong prognostic indicator of r esponse to chemotherapy and survival in AML, MDS, and CLL. The usual a ssociation of p53 mutations to loss of the nonmutated P53 allele, in t hose disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells. (C) 1994 by The American Society of Hematology.