TP53 mutation and survival in chronic lymphocytic leukemia.
ABSTRACT The precise prognostic impact of TP53 mutation and its incorporation into treatment algorithms in chronic lymphocytic leukemia (CLL) is unclear. We set out to define the impact of TP53 mutations in CLL.
We assessed TP53 mutations by denaturing high-performance liquid chromatography (exons 2 to 11) in a randomized prospective trial (n = 375) with a follow-up of 52.8 months (German CLL Study Group CLL4 trial; fludarabine [F] v F + cyclophosphamide [FC]).
We found TP53 mutations in 8.5% of patients (28 of 328 patients). None of the patients with TP53 mutation showed a complete response. In patients with TP53 mutation, compared with patients without TP53 mutation, median progression-free survival (PFS; 23.3 v 62.2 months, respectively) and overall survival (OS; 29.2 v 84.6 months, respectively) were significantly decreased (both P < .001). TP53 mutations in the absence of 17p deletions were found in 4.5% of patients. PFS and OS for patients with 17p deletion and patients with TP53 mutation in the absence of 17p deletion were similar. Multivariate analysis identified TP53 mutation as the strongest prognostic marker regarding PFS (hazard ratio [HR] = 3.8; P < .001) and OS (HR = 7.2; P < .001). Other independent predictors of OS were IGHV mutation status (HR = 1.9), 11q deletion (HR = 1.9), 17p deletion (HR = 2.3), and FC treatment arm (HR = 0.6).
CLL with TP53 mutation carries a poor prognosis regardless of the presence of 17p deletion when treated with F-based chemotherapy. Thus, TP53 mutation analysis should be incorporated into the evaluation of patients with CLL before treatment initiation. Patients with TP53 mutation should be considered for alternative treatment approaches.
- SourceAvailable from: Clemens-Martin WendtnerLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2013; · 10.16 Impact Factor
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ABSTRACT: TP53 mutations occur in several cancers including hematologic malignancies and correlate with poor prognosis. To investigate their impact in adult acute lymphoblastic leukemia, we analyzed 98 newly-diagnosed cases using the AmpliChip p53 Research Prototype Test. Mutations were identified in 8/98 patients (8.2%). Within the 62 B-lineage cases, 4 were mutated (6.4%): 3 (12.5%) were negative for recurrent fusion genes and 1 was BCR/ABL+ (4%). Within the 36 T-lineage cases, 4 - all negative for recurrent fusion genes - carried TP53 mutations (11.1%). Overall, mutations were found in 14% of the 51 cases negative for recurrent fusion genes; within such subgroup, response to induction treatment was evaluable in 43 patients: 6 were refractory and 3 of them (50%) were TP53 mutated. Our results suggest that TP53 mutations are important genetic abnormalities in adult acute lymphoblastic leukemia negative for recurrent fusion genes that might impact negatively on response to induction treatment.Haematologica 02/2013; · 5.94 Impact Factor
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ABSTRACT: Genetics and molecular genetics have contributed to clarify the biological bases of the clinical heterogeneity of chronic lymphocytic leukemia. In recent years, our knowledge of the molecular genetics of chronic lymphocytic leukemia has significantly broadened, offering potential new clinical implications. Mutations of TP53 and ATM add prognostic information independently of fluorescence in situ hybridization cytogenetic stratification. In addition, next generation sequencing technologies have allowed previously unknown genomic alterations in chronic lymphocytic leukemia to be identified. Mutations of NOTCH1, SF3B1 and BIRC3 have been associated with short time to progression and survival. Each of these lesions recognizes a different distribution across different clinical phases and biological subgroups of the disease. The clinical implications of these molecular lesions are in some instances well established, such as in the case of patients with TP53 disruption, who should be considered for alternative therapies/allogeneic stem cell transplant upfront, or in patients with ATM disruption, who are candidates to rituximab-based immunochemotherapy. On the contrary, NOTCH1, SF3B1 and BIRC3 mutations appear to have a specific significance, the clinical value of which is currently being validated, i.e. association to Richter syndrome transformation for NOTCH1 mutations, and short progression-free survival after treatment for SF3B1 mutations. Certainly, these new lesions have helped clarify the molecular bases of chronic lymphocytic leukemia aggressiveness beside TP53 disruption. This review covers the recent advancements in our understanding of the molecular genetics of chronic lymphocytic leukemia and discusses how they are going to translate into clinical implications for patient management.Haematologica 05/2013; 98(5):675-85. · 5.94 Impact Factor