CLINICAL-SIGNIFICANCE OF P53 MUTATIONS IN NEWLY-DIAGNOSED BURKITTS-LYMPHOMA AND ACUTE LYMPHOBLASTIC-LEUKEMIA - A REPORT OF 48 CASES

Purpose: To correlate the presence of p53 mutations and initial charac teristics, response to chemotherapy, and survival in newly diagnosed B urkitt's lymphoma (BL) and Burkitt's acute lymphoblastic leukemia (L(3 ) ALL). Patients and Methods: Forty-eight patients with newly diagnose d BL or L(3) ALL, most of whom were treated with very intensive regime ns, including early CNS disease treatment, were studied. Detection of p53 mutations was made by single-strand conformation polymorphism (SSC P) analysis of exons 5 to 8 of the gene, and mutations were determined by direct sequencing of exons with abnormal SSCP findings. Comparison of outcome between mutated and nonmutated cases was mode in all patie nts and also after excluding five patients who received therapeutic re gimens considered as suboptimal and one patient who died of AIDS while in complete remission (CR), as those six patients had no p53 mutation s. Results: A point mutation was found in nine patients (19%), and con sisted of a missense mutation in seven and a chain-terminating mutatio n in two. SSCP, sequence, and cytogenetic analysis strongly suggested that eight of nine patients with mutations had retained the normal p53 allele, which had been lost in the remaining patient. These findings were confirmed by fluorescence-in-situ hybridization (FISH) with a p53 -specific probe in two patients, including the one who had lost the no rmal p53 allele. Unexpectedly, mutations were significantly less frequ ent in patients with disseminated disease, ie, L(3) ALL or stage IV BL (four of 35, 11%), than in more localized forms, ie, BL stage I, II, or III (five of 13, 38%) (P = .03). CR rates were similar in mutated ( 78%) and nonmutated cases (78%). The actuarial disease-free intervol ( DFI) after 12 months and actuarial survival rates after 24 months were 49% and 66%, respectively, in patients with mutations, and 73% and 48 %, respectively, those without mutations. The differences were not sig nificant. Conclusion: Our findings suggest that, contrary to what is s een in most other neoplasias, p53 mutations in newly diagnosed BL and L(3) ALL are not associated with extensive tumor mass or poor response to intensive therapeutic regimens. It is hypothesized that this diffe rence with most tumors could be due to the fact that p53 mutations in BL. and L(3) ALL are generally associated with persistence of a normal residual p53 allele, contrary to what is observed in the majority of tumors. J Clin Oncol 13:812-820. (C) 1995 by American Society of Clini cal Oncology.