Disruption of TP53 function by Point Mutations and Deletions Is Associated with An Increased Risk of Disease Progression within Previously Treated, Relapsed Chronic Lymphocytic Leukemia Patients

Abstract Abstract 2445 Chronic lymphocytic leukemia (CLL) patients with a deletion of the TP53 tumor supressor gene located at 17p13 have a poor prognosis in first line chemotherapy regimens. Recent studies indicated somatic TP53 mutations as a prognostic factor in CLL independent of 17p13 deletion status. We aimed to further characterize the prognostic value and the impact of TP53 mutations on progression-free survival (PFS) in the presence and absence of a 17p13 deletion in previously treated and relapsed CLL patients within an international phase III clinical study comparing Fludarabine and Cyclophosphamide with or without Rituximab (FC versus R-FC: REACH trial). We analyzed 457 patients at diagnosis for mutations in the TP53 gene using a combination of a microarray-based resequencing assay (AmpliChip p53 Test, Roche Molecular Systems, USA.) and Sanger sequencing of TP53 exons 2–10. The data were correlated with clinical and biologic markers as well as with interphase fluorescence in situ hybridization (FISH) and with PFS. Association of the clinical data with PFS was assessed by Cox proportional hazard models. To estimate the functional significance of the individual TP53 mutations we used the IARC TP53 database. TP53 mutations (n=60) were detected in 52 of 457 patients (11.4%) and included 42 missense, 4 nonsense, 8 frameshift mutations, 2 in-frame deletions and 4 mutations in splice sites. Among other clinical variables, only 17p13 deletion was associated with TP53 mutations: 27 of 52 TP53 mutated patients had a 17p13 deletion (concordance rate: 52%, Fisher's test p<0.001). Median PFS for patients with TP53 mutations (n=52, 13 months, HR=1.9 (1.4–2.7), p<0.001) was significantly shorter as compared to patients without TP53 mutations (n=480, 27 months). In a sub-group analysis, chemoimmunotherapy including Rituximab did not significantly improve the PFS of patients with TP53 mutations. Multivariate analysis including treatment arm, Binet stage, age, IGVH mutational status, 17p13 deletion and TP53 mutation status confirmed TP53 mutation status (HR-TP53=1.7 (1.1–2.6), p=0.009) as a prognostic factor for PFS independent of 17p13 deletion status (HR-17p=1.7 (1.1–2.7), p=0.024) and with a similar effect size. The other independent prognostic factors were treatment (HR=0.61 (0.48–0.76), p<0.001), Binet stage (HR=1.64 (1.3–2.1), p<0.001) and IGVH mutational status (HR=2.4 (1.85–3.1), p<0.001). To further dissect the contribution of TP53 mutation and 17p13 deletion on PFS, we considered a multivariate analysis comparing patients with both TP53 mutation and 17p13 deletion (n=28), with only 17p13 deletion (n=9), with a dominant negative TP53 mutation or multiple TP53 mutations (n=8) or with a single TP53 mutation (n=16) against patients without TP53 abnormalities (n=271), adjusted for treatment, Binet stage, age and IGVH mutational status. Patients with a predicted biallelic disruption of TP53 either by a TP53 mutation in combination with a 17p13 deletion (HR: 2.8 (1.8,4.2), p=<0.001) or patients with a dominant negative TP53 mutation as predicted by the IARC TP53 database or multiple TP53 mutations (HR=3.26 (1.5,7.1), p=0.003) had a risk similar in size and which was quite high for disease progression (the reference to calculate the risk, here and in the following, is always the group of patients without TP53 abnormalities). The risk slightly decreased for patients with only a deletion 17p13 (HR=2.2, (1.1–4.3), p=0.021). Very interestingly, single TP53 mutations showed a much lower risk for disease progression (in this case not even significant) (HR=1.61 (0.9–2.8), p=0.084) especially compared to the risk conferred by a biallelic disruption. In this large cohort of previously treated CLL patients, complete disruption of TP53 function (by a combination of a 17p13 deletion and a TP53 mutation, through dominant negative TP53 mutations or through multiple TP53 mutations) was associated with a higher risk for disease progression. Prognosis of patients with a single TP53 mutation was not significantly different from patients without TP53 aberrations. It remains to be shown whether CLL patients with a single TP53 mutation are at a higher risk of acquiring additional mutations of TP53 during disease progression. Prognostic stratification of previously treated CLL patients should include a routine molecular TP53 mutational analysis in addition to deletion analysis of the TP53 locus by FISH. Disclosures: Dufour: Roche: Research Funding. Bohlander:Roche: Research Funding. Spiekermann:Roche: Research Funding. Schneider:Roche: Research Funding. Hiddemann:Roche: Research Funding. Truong:Roche: Employment. Patten:Roche: Employment. Wu:Roche: Employment. Dmoszynska:Mundipharma:; Roche: Honoraria. Robak:Centocor Ortho Biotech Research & Development: Research Funding. Geisler:Roche: Speakers Bureau. Dornan:Genentech: Employment. Lin:Genentech: Employment. Yeh:Genentech: Employment. Weisser:Roche: Employment. Duchateau-Nguyen:Roche: Employment. Palermo:Roche: Employment.

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The Broad Spectrum of TP53 Variants in CLL: NGS Analysis of 573 Pathogenic TP53 Variants

Blood ◽

10.1182/blood-2019-130907 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3021-3021

Author(s):

Gregory Lazarian ◽

Floriane Theves ◽

Myriam Hormi ◽

Virginie Eclache ◽

Stéphanie Poulain ◽

...

Keyword(s):

Tumor Progression ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Fish Analysis ◽

Snp Analysis ◽

Advisory Committees ◽

Exon 2 ◽

Tp53 Mutations ◽

Mutational Status

TP53 aberrations, including somatic mutations of TP53 gene or 17p deletion leading to the loss of the TP53 locus, are a major predictive factor of resistance to fludarabin based chemotherapy in chronic lymphocytic leukemia (CLL) and remain an adverse prognostic factor in the chemofree era. Therefore, detection of TP53 alteration before each new line of treatment is required for theranostic stratification. In order to better characterize the distribution and combination of the TP53 variants in CLL, we collected the TP53 sequencing data of 343 patients harboring TP53 mutations from centers of the French Innovative Leukemia Organization-CLL (FILO) and established a large data base of 573 TP53 mutations. Mutations were identified through NGS sequencing (covering exon 2 to 11) allowing the detection of low frequency variants down to 1% VAF. Several distinct low VAF mutations were orthogonally confirmed by digital PCR. TP53 variants were analyzed through UMD_TP53 data gathering 90 000 TP53 mutations from all type of cancers. IGHV mutational status and FISH analysis were available for 224 and 176 patients respectively. Using ACMG criteria from the UMD_TP53 database, we confirmed that 523 could be classified as pathogenic, 42 were likely pathogenic and 8 were VUS (Variants of Unknown Significance). As expected, the mutation distribution along the p53 protein exhibited a clustering of variants in the DNA binding domain of the protein. We also confirmed the presence of a specific hotspot at codon 234 (6%) which is noticeable in other CLL cohorts but absent in solid tumors. 431 TP53 variants led to the expression of a mutant protein whereas the remaining 142 led a TP53 null phenotype. For 8 patients without 17p deletion and a mutation VAF larger than 50%, SNP analysis indicate that these tumors had a copy number neutral loss of heterozygosis at 17p with a duplication of the mutant allele leading to homozygous mutations of TP53. When focusing on the allele burden of TP53 mutations, 264/573 (46%) variants had an allele frequency <10%. Even if they were predominantly found in polymutated cases, presence of only low VAF (<10%) mutations was evidenced in 74 (21%) patients (50 patients with a single TP53 mutation and 24 patients with more than one). All these cases would have been missed by conventional sequencing. Among the 343 patients, 113 (33%) were poly-mutated and harbored more than one pathogenic TP53 variants (2 to 11 variants per patient): 57 (16,7 %) had 2 variants, 32 (9,3%) had 3, 10 had 4 (3%) and 14 patients (4%) had 5 to 11 variants. Using both long range sequencing and in silico analysis, we could show that all these variants were distributed in different alleles supporting an important intratumoral heterogeneity and a strong selection for TP53 loss of function during tumor progression in these patients. Null variants were rarely found as single alteration: only 46 patients (13,4%) patients harbored a single null mutation. Null mutations were predominantly found in patients with multiclonal mutations (87% with 4 or more). Median size of variants significantly decreased with the number of mutations and most of low VAF (less than 10%) variants were found in multiclonal combinations. Multiclonal mutations were predominantly found in previously treated patients (41% treated versus 10 % untreated) but whether all these variants preceded treatment and were further selected is currently unknown. We observed that 71,5 % of patients were IGHV unmutated and multiclonal mutations were surprisingly more frequent in mutated IGHV cases than in unmutated ones. Only 50% of cases carried a 17p deletion, highlighting again the importance of testing for TP53 mutations in addition to FISH analysis. Presence or absence of 17p deletion was unrelated to the number of TP53 mutations. Taken together these observations suggest that the TP53 mutational landscape in CLL is very complex and can involve multiple mechanisms, converging to a total loss of TP53 function and tumor progression. NGS provides a powerful tool for detecting all these alterations including variants with low VAF and should become a standard for CLL screening prior to each line of treatment. Disclosures Leblond: Amgen: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Letestu:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Cymbalista:Abbvie: Honoraria; Roche: Research Funding; Sunesis: Research Funding; Gilead: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

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A Phase II Study of Chlorambucil Plus Rituximab Followed by Maintenance Versus Observation In Elderly Patients with Previously Untreated Chronic Lymphocytic Leukemia: Results of the First Interim Analysis

Blood ◽

10.1182/blood.v116.21.2462.2462 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2462-2462 ◽

Cited By ~ 3

Author(s):

Robin Foa ◽

Stefania Ciolli ◽

Francesco Di Raimondo ◽

Giovanni Del Poeta ◽

Francesco Lauria ◽

...

Keyword(s):

Elderly Patients ◽

Interim Analysis ◽

Overall Response Rate ◽

Response Rate ◽

Lymphocytic Leukemia ◽

Induction Phase ◽

First Line ◽

Mutational Status ◽

Igvh Mutational Status ◽

Binet Stage

Abstract Abstract 2462 Background: Two of the largest trials ever conducted in patients with chronic lymphocytic leukemia (CLL) have shown that the addition of rituximab to fludarabine plus cyclophosphamide (R-FC) significantly improves outcome. However, myelotoxicity and immunosuppression limit the use of this regimen in patients with impaired performance status and pre-existing co-morbidities, predominantly in the elderly. Chlorambucil (CLB) remains a first-line treatment option for such patients. The use of CLB in combination with R is thus an attractive therapeutic option in view of the potentially increased activity compared to CLB alone and the likely good tolerability. This study was designed to determine whether the R-CLB combination is feasible and beneficial as first-line treatment for elderly patients with CLL and to define the role of maintenance R. Patients and Methods: Between October 2008 and January 2010, 97 elderly patients with untreated CD20+ CLL requiring therapy according to the IWCLL criteria were enrolled into the protocol. CLB treatment was administered every 28 days for up to 8 courses at a dose of 8 mg/m2/day p.o. on days 1–7 combined with 375 mg/m2 R for cycle 3 and 500 mg/m2 for cycles 4–8. Responsive patients were randomized to R maintenance (375 mg/m2 every 2 months for 2 years) versus observation. At baseline, blood samples were taken for FISH analysis, IgVH mutational status and expression of Zap-70 and CD38. Minimal residual disease (MRD) was planned to be evaluated on peripheral blood (PB) and bone marrow (BM) cells by four-color flow cytometry and, when required, by PCR. The primary endpoint was the overall response rate at the end of the induction phase defined according to the IWCLL 2008 on the intention-to-treat (ITT) population (all enrolled patients who received at least 1 dose of R). Secondary endpoints included the adverse event (AE) profile, progression-free and overall survival. Results: These are the data of the planned interim analysis based on the first 54 evaluable patients from 19 Italian centers, including tumor response at the end of the induction phase and safety. The median age of patients was 70.5 years (range 61–84): 14.8% were between 61 and 64, 31.5% between 65 and 69, 31.5% between 70 and 74, 16.7% between 75 and 79, and 5.6% were ≥80 years; thus, 53.8% of patients were over the age of 70; 70.4% were males; 25.9% were Binet stage A, 57.4% stage B and 16.7% stage C. The overall incidences of trisomy 12 and abnormalities of 13q, 11q23 and 17p13 were 24.5%, 52.8%, 20.8% and 5.7%, respectively; 7.5% of patients had p53 mutations. Of the 51/54 patients analyzed for the IgVH mutational status, 64.7% were unmutated; of the 53/54 patients studied, 39.6% were CD38+ and 71.7% were Zap-70+. The overall response rate on an ITT analysis was 81.4% (44/54 patients); a CR assessed by CT scan and trephine immunohistochemistry was found in 16.7% of cases (9 patients: 4 in Binet stage A, 3 in stage B and 2 in stage C), a CRi in 3.7% (2 patients), a nPR in 1.9% (1 patient) and a PR in 59.3% (32 patients). Eight of the 9 CR cases were investigated for MRD by flow cytometry and all proved positive: 6/8 had MRD levels <10−3 in the PB and 2/8 in the BM. A progressive disease was recorded in 2 patients (4%) and a stable disease in 2 (4%). Six patients (11%) were not evaluable for response: 1 investigator's decision, 2 AEs (1 R infusion-related reaction and 1 unrelated episode of dyspnea) and 3 SAEs (1 CLB-related anemia, 1 endometrial in situ carcinoma and 1 anaplastic oligoastrocytoma). Seven SAEs occurred in 7 patients during courses 3–8. Only 1 SAE was related to treatment (1 CLB-related anemia). The most common toxicities were neutropenia (31.5% of patients, 8.9% of cycles) and thrombocytopenia (14.8% of patients, 5.7% of cycles). Grade III-IV neutropenia was present in 16.7% of patients and in 3.8% of cycles. No grade III-IV infections occurred. A median of 85.4 R-CLB courses was administered with 85.1% of patients completing the planned treatment; 15.3% of cycles needed a CLB dose reduction (12.9% due to toxicity, mainly neutropenia and thrombocytopenia). Conclusions: Overall, the results of the interim analysis indicate that R-CLB is active and well tolerated in elderly patients with previously untreated CLL. Disclosures: Foa: Roche: Consultancy, Speakers Bureau. Montillo: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Runggaldier: Roche S.p.A. Monza: Employment. Gamba: Roche S.p.A. Monza: Employment.

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Heat Shock Protein 90 (Hsp90) Activity Status Is An Independent Prognostic Marker in Chronic Lymphocytic Leukemia (CLL) and Correlates with IgVH Mutational Status, ZAP-70 Expression and Time to First Treatment

Blood ◽

10.1182/blood.v118.21.2544.2544 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2544-2544

Author(s):

Januario E. Castro ◽

Juan S. Barajas-Gamboa ◽

Julio A. Diaz-Perez ◽

Lina M. Ariza-Serrano ◽

Johanna Melo-Cardenas ◽

...

Keyword(s):

Disease Progression ◽

Progressive Disease ◽

Prognostic Markers ◽

Hsp90 Inhibitor ◽

Lymphocytic Leukemia ◽

Independent Prognostic Marker ◽

In Vitro Sensitivity ◽

Mutational Status ◽

Igvh Mutational Status

Abstract Abstract 2544 The clinical presentation of chronic lymphocytic leukemia (CLL) is variable and includes at least two distinct clinical subtypes: indolent or progressive disease. Several prognostic markers such as the mutational status of the IgVH genes or ZAP-70 expression identify patients that will have more aggressive clinical courses. We have previously reported that ZAP-70 expression in CLL requires the support and stability provided by the Hsp90 activated complex (Hsp90-AC) and that Hsp90 inhibitors induce apoptosis in CLL cells preferentially in patients with high–risk/rapid progressive disease. Hsp90 requires the conformation of a multimeric complex with other co-chaperones (Hop, p23) to become active and function as a chaperone for mutated, over-expressed, misfolded or constitutively activated proteins. However, to measure Hsp90-AC activity is challenging and requires protein assays that are semi-quantitative and not always can provide a functional read out. To address this problem we designed a test to measure Hsp90-AC by taking advantage of the higher avidity of this complex to bind Hsp90 inhibitors such as 17-AAG. We hypothesize that Hsp90-AC activity is an independent prognostic marker of disease progression in CLL and to test this we measured the ability of 17-AAG to inhibit Hsp90-AC and promote apoptosis in vitro in a cohort of previously untreated CLL patients. This evaluation was performed in samples collected at the time of diagnosis and the results were correlated with the time from diagnosis to first treatment (t-Tx1) as well as the presence of other known prognostic markers. Ninety-five previously untreated CLL patients were included in this cohort. In vitro sensitivity/apoptosis to Hsp90-AC inhibition using 17-AAG (1μg/ml) was measured by flow cytometry using DiOC6 and PI after 48 hours of incubation. Only samples with more than 60% viability were included and we selected a cut-point of ≥ 53% induction of apoptosis to determine if a sample was sensitive or not to Hsp90-AC inhibition (This cut-point was selected using a ROC analysis for optimal diagnostic performance). We found that 37 patients (39%) were sensitive to 17-AAG. These patient had a median time from diagnosis to first treatment (t-Tx1) of 7 years compared to 4.2 years in patients that were resistant to 17-AAG (p=0.04). In addition, 37 patients (39%) had unmutated IgVH genes with a median t-Tx1 of 8.7 years compared to 4.2 years in patients with mutated IgVH genes (p=0.02) and 41 patients (43%) had high levels of ZAP-70 expression (>20% by flow cytometry) and this group of patients had a median t-Tx1 of 7 years vs. 4.2 years in ZAP-70 negative patients (p=0.03). We evaluated the association between the degree of Hsp90-AC inhibition (17-AGG sensitivity) and IgVH mutational status and found a strong correlation between these two variables with shorter t-Tx1 in patients that were IgVH unmutated and sensitive to Hsp90 inhibitor (p=0.0003). We found a similar strong correlation between ZAP-70 expression and sensitivity to Hsp90-AC inhibitor (p=0.003). In our patient cohort, we saw that IgVH, ZAP-70 and Hsp90 inhibitor sensitivity are independent prognostic markers in CLL (Cox regression, p=0.002). We found that the sensibility and specificity of ZAP-70 test for high-risk CLL (sensitivity 81.1% [95% IC 67–95%] and specificity 77.6%[95% IC 65–90%]) was increased when the Hsp90-AC inhibitor sensitivity test was added (sensitivity 87% [95% IC 71–100%] and specificity 91%[95% IC 79–100%]). In conclusion, in vitro inhibition of Hsp90-AC in CLL using 17-AAG is an independent prognostic maker and strong predictor of the need for treatment. Hsp90-AC inhibition showed a high correlation with IgVH mutational status and ZAP-70 expression. Additionally, patients sensitive to 17-AAG whose leukemic cells also highly express ZAP-70 appear to have the worst prognosis with the shortest t-Tx1. Our data suggest that in vitro sensitivity to 17-AAG at the time of diagnosis serves as a quantitative surrogate marker for Hsp90-AC activity and correlates with disease progression in CLL. This is the first time that such correlation has been established in a cohort of cancer patients and shows the relevance of the Hsp90 chaperone system in cancer biology and disease progression. Disclosures: No relevant conflicts of interest to declare.

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MicroRNA-29c and 223 Are Powerful Prognostic Factors for Chronic Lymphocytic Leukemia and Improve Risk Stratification When Combined with ZAP70 and LPL in a qPCR Score.

Blood ◽

10.1182/blood.v112.11.1066.1066 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1066-1066

Author(s):

Basile Stamatopoulos ◽

Nathalie Meuleman ◽

Dominique Bron ◽

Benjamin Haibe-Kains ◽

Pascale Saussoy ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Lymphocytic Leukemia ◽

Noncoding Rna ◽

Poor Prognosis ◽

Lymphocytic Leukemia ◽

Early Therapy ◽

Mutational Status ◽

Igvh Mutational Status ◽

Binet Stage

Abstract Background: MicroRNAs (or miR) are a novel class of small noncoding RNA involved in gene regulation. Aberrant microRNA expression has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Currently, the heterogeneous evolution of this disease can be predicted by several prognostic factors. Nevertheless, a better individualization of the outcome in a given patient is still of utmost interest. Methods: In the current study, we investigated the expression of two microRNAs, miR-29c and miR-223, compared them to other biological or clinical markers and proposed a quantitative real-time PCR (qPCR) score to better assess CLL outcome. All cut-offs were calculated by ROC curve analysis maximising the correlation with the immunoglobulin variable heavy chain (IgVH) mutational status; statistical differences were evaluated by Mann Whitney test or Kruskal-Wallis test ; treatment-free (TFS) and overall (OS) survival differences were investigated by log-rank test or Cox proportional hazard ratio (HR). Results: miR-29c and miR-223 expression decreased significantly with progression along Binet Stage A to C (P=0.0010 and P=0.0183, respectively), and were significantly lower in poor prognosis subgroups defined by cytogenetic abnormalities, IgVH mutational status, lymphocyte doubling time, solubleCD23, β2-microglobulin, ζ-associated protein 70 (ZAP70), lipoprotein lipase (LPL) and CD38 expression. Furthermore, miR-29c and miR-223 could predict TFS (n=110, P=0.0015 and P<0.0001, respectively) and OS (n=110, P=0.0234 and P=0.0008, respectively). Regarding all these results, we developed a qPCR score (from 0 to 4 poor prognostic markers) combining miR-29c, miR-223, ZAP70 and LPL in order to stratify treatment and death risk in a 110 patient cohort with a median follow-up of 72 months (range, 2–312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of >312, 129, 80, 36 and 19 months, respectively (HR=17.00, P<0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of >312, 183 and 106 months, respectively (HR=13.69, P=0.0001). Interestingly, during the first 50 months after diagnosis, only 10% of patients with a 0/4 score required a treatment, when compared to 100% of the 4/4. Furthermore, during the total follow-up (312 months), patients with a 4/4 score had a 27-fold higher risk to be treated and a 31-fold higher risk to die comparing to patients with a 0/4 score. This score was validated by a 10-fold cross-validation (prediction accuracy of 82%). Finally, in Binet stage A patients (n=77), this score remained relevant and significant for TFS and OS prediction (HR=18.56, P<0.0001 and HR=12.5, P=0.0068, respectively). Conclusions: we showed that (i) miR-29c and miR-223 levels were decreased in poor prognosis patients regarding several well-known prognostic factors; (ii) a low level of these two microRNAs is thus associated to disease aggressiveness, tumor burden and poor clinical evolution; (iii) we also showed that these two microRNAs could predict TFS and OS; (iv) we proposed a qPCR score to better individualize evolution of a particular CLL patient. This score will help to identify patients who will need early therapy and require thus a closer follow-up.

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Genomic Mechanisms of 17p / TP53 Loss in Primary “ultra High-risk” and Refractory Chronic Lymphocytic Leukemia: Results from the CLL2O Trial

Blood ◽

10.1182/blood.v124.21.2184.2184 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2184-2184

Author(s):

Veronica Teleanu ◽

Jennifer Edelmann ◽

Claudia Haferlach ◽

Stefan Ibach ◽

Eugen Tausch ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Tp53 Mutation ◽

Lymphocytic Leukemia ◽

Chromosome 17 ◽

Tp53 Mutations ◽

Ultra High Risk ◽

Treatment Naïve ◽

Donor Chromosome

Abstract Background: Unraveling the cytogenetic background helped to decipher the molecular basis of many hematologic cancers and to develop specific therapies. Recently, using chromosome banding analysis (CBA), jumping translocations were identified as a cause of 17p loss in multiple myeloma, providing new insights into the origin of clonal evolution and copy number alterations (CNA) (Sawyer et al, Blood 2014). In chronic lymphocytic leukemia (CLL) the genomic mechanisms leading to 17p loss are not fully understood. Aims: Characterization of underlying mechanisms of 17p loss using CBA and correlation with other clinicobiological features in “ultra high-risk” CLL. Methods: Samples from 112 patients (pts.) with refractory and/or 17p- CLL enrolled in the multicenter CLL2O trial were screened for CNAs by Affymetrix 6.0 SNP array analysis of CD19 sorted CLL cells and for chromosomal abnormalities by CBA using CpG oligonucleotide and interleukin-2 stimulation. Results: Considering both CBA and SNP data, 728 aberrations resulted in a mean of 6.5/case. 89 (79%) pts. had 17p deletion and 83 (74%) TP53 mutation. Regarding the origin of 17p/TP53 loss, 6 distinct types of rearrangements could be delineated: 1) whole arm translocations (WAT) 2) jumping translocations (JT) 3) dicentric chromosomes (DC) 4) cytogenetically balanced translocations (CBT) 5) other unbalanced translocations and 6) interstitial 17p deletions. WAT were identified in 33/112 (30%) cases and 30/33 (91%) involved chromosome 17 leading to 17p loss. Chromosomes involved ≥ 2 times in an unbalanced WAT were der(17;18)(q10;q10) (8, 24%), der(8;17)(q10;q10) (5, 15%), der(15;17)(q10;q10) (4, 12%), i(17)(q10) (4, 12 %), der(17;22)(q10;q10) (2, 6%). JT were identified in 11 (10 %) cases, 6 showing jumping WAT with 17q as donor chromosome, 1 case with breakpoints located in the pericentromeric regions of chromosome 17p11 (donor chromosome) and the receptor chromosomes 4p14 and 16p11. In 4 cases, initially a WAT involving 17q occurred and subsequently the partner chromosome “jumped off” leaving a 17p deletion behind. DC were detected in 19 pts., 8 with breakpoint in 17p11, 7/8 with TP53 mutation. Of note, all cases had the breakpoint on chromosome 17 in 17p11 indicating a fragile site affecting the pericentromeric region. Interestingly, of a total of 382 translocations observed by CBA, only 32 were CBT and except for those involving the IGH and IGK/L loci (n=6) all were random. 17p involvement in CBT was detected in 4 cases, 3 had TP53 deletion and all were TP53 mutated. Of the unbalanced translocations, der(17)t(8;17) was identified in 5 pts. simultaneously generating 8q gain. Nevertheless, breakpoints on chromosome 17p covered cytobands 17p11-13 and on chromosome 8, 8q11-22, one case having the breakpoint telomeric to the TP53 locus and no TP53 mutation, pointing to other putative candidate genes on 17p. In 36/112 (32%) cases, 17p deletion was induced by random rearrangements. Interstitial 17p deletions were identified in only 9/112 (8 %) cases. According to the inclusion criteria of the trial, 36/112 (32%) pts. had 17p deletion and were treatment-naïve while 76/112 (68%) were relapsed or refractory to fludarabine or bendamustine based therapy, 53/76 (70%) having a 17p deletion. Treatment naïve pts. had a mean of 7.36 aberrations/case and pretreated pts. 6.09/case. Focusing on WAT and JT, 18/33 (54%) pts. with WAT and 7/11 (63%) pts. with JT were pretreated whereas 57/78 (73%) pts. in the other cytogenetic subgroups had prior therapy exposure. Considering other genomic features, WAT and JT occurred almost exclusively within complex karyotypes (≥3 chromosomal aberrations), 31/33 WAT and 10/11 JT, were IGHV unmutated, 30/33 WAT and 11/11 JT and harbored TP53mutations, 29/33 WAT and 10/11 JT. Conclusions: “Ultra high-risk” CLL pts. are characterized by a high genomic complexity as compared to standard risk treatment-naïve CLL pts. (CLL8 trial with 1.8 CNAs/case). Previous genotoxic therapy had no influence on the total number of aberrations or the underlying mechanism, suggesting an intrinsic genomic instability of the tumor cells with TP53 alterations. WAT and JT emerged as nonrandom aberrations involved in 17p loss. Given the strong association of TP53 deletion with TP53 mutations of the remaining allele, one may speculate that TP53 mutations precedes TP53 deletion by disrupting the normal DNA repair mechanisms permitting incorrect recombinations. Disclosures Stilgenbauer: Amgen: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.

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Low-Burden TP53 Mutations Occur in Chronic Phase of Myeloproliferative Neoplasms Regardless of Hydroxyurea Administration, Disease Type, and JAK2 Status

Blood ◽

10.1182/blood.v128.22.4284.4284 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4284-4284

Author(s):

Blanka Kubesova ◽

Sarka Pavlova ◽

Jitka Malcikova ◽

Jitka Kabathova ◽

Lenka Radova ◽

...

Keyword(s):

Overall Survival ◽

Disease Progression ◽

Research Funding ◽

Tp53 Mutation ◽

Chronic Phase ◽

Disease Type ◽

Leukemic Transformation ◽

Tp53 Mutations ◽

Mutation Burden

Abstract Myeloproliferative neoplasms (MPN) are characterized by abnormal proliferation of myeloid lineages and a tendency toward leukemic transformation. Inactivation of tumor suppressor TP53 has been repeatedly associated with MPN transformation into secondary acute myeloid leukemia (sAML), but no fully expanded TP53 mutated clones in chronic phase of MPN were reported. The link between TP53 mutations and widely used cytoreductive treatment by hydroxyurea (HU) still remains controversial. To which extent TP53 mutations represent a risk of disease progression is not known. We aimed to search for low-burden TP53 mutated subclones in chronic-phase-MPN patients and to correlate presence of these clones with therapy, disease course, and other clinical features. In total we analyzed 220 patients by ultra-deep next generation sequencing (NGS). We detected TP53 mutations in 39 (18 %) patients with variant allelic frequency of 0.1-16.3 % at the first examination. The analysis of 136 patients treated with hydroxyurea or other drugs (anagrelide (ANA), interferon α (IFN)) for more than 4 years, as well as a group of 84 patients untreated by cytoreductive drugs, showed that TP53 mutations occurrence in chronic phase is independent of hydroxyurea use, disease type, and JAK2/CALR/MPL status. Mutations were found in 17/72 (24 %) HU treated patients, in 11/64 (17 %) patients treated by other drugs, and in 11/84 (13 %) untreated patients. Median size of mutated clones was 0.5 % and was not influenced by previous treatment. In 10 patients we found more than one mutation. In patients harboring TP53 mutations, retrospective samples were examined if available to explore the clonal evolution of TP53 mutated clones. The respective TP53 mutations were found in 13/20 cases analyzed; out of them, in 4 cases the mutation was found even in a diagnostic sample. Follow-up samples were examined in 28 patients with TP53 mutations and the mutation burden changed during the monitored time in majority of patients; however, the expansion into dominant clone was observed in one patient only. When all data from retrospective and prospective analyses taken together (30 patients), the median follow-up was 7.2 years. TP53 mutation burden tended to increase in 14 patients. In 6 patients the mutation burden remained stable and in 4 patients it fluctuated. In 6 patients the mutated clone size decreased; out of them in 2 originally very low-burden mutations (0.2 %) were not detectable in samples taken 15 and 3.4 years later. We did not observe any correlations of different patterns in TP53 mutation changes with therapy or other clinical characteristics (disease type, driver mutation, time from diagnosis, treatment response). Further, we assessed the TP53 mutation impact on overall survival and leukemic transformation. The mutations did not negatively affect disease progression or overall survival either from diagnosis or from mutation identification. sAML developed in 2 patients with TP53 mutations 17.9 (treated with IFN) and 8.3 (treated with HU) years from diagnosis. In the latter patient, the sAML developed from a different clone as it was TP53-wt, JAK2-wt, although 2 TP53 mutated clones within JAK2 mutated clone were detected in chronic phase. On the other hand, we have observed another interesting case where the TP53 mutation burden grew rapidly from 10 % up to nearly 100 % during the follow-up. In contrast to published data, this patient did not show any clinical signs of disease progression for 2 years after the expansion and died of MPN unrelated cause. In summary, using highly sensitive method we showed that low-burden TP53 mutations are present in MPN chronic phase. Neither their presence nor their size is associated with previous therapy and has impact on overall survival or leukemic transformation. Monitoring of TP53 mutations during the disease course showed that their clonal development is rather variable; nevertheless, TP53 minor mutations may represent a pool for future clonal evolution. Supported by MZ CR-RVO (FNBr, 65269705), MUNI/A/1028/2015, H2020 692298, MZO AZV 15-31834A, 15-30015A, MEYS LQ1601 and LM2015064. Disclosures Gisslinger: Baxalta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees.

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Low Expression of MiR-34a in Previously Treated Chronic Lymphocytic Leukemia Patients Is Limited to Patients with a Complete Disruption of TP53 Function and Does Not Correlate with MDM2 SNP309,

Blood ◽

10.1182/blood.v118.21.3521.3521 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3521-3521

Author(s):

Annika Dufour ◽

Stefan K Bohlander ◽

Evelyn Zellmeier ◽

Gudrun Mellert ◽

Karsten Spiekermann ◽

...

Keyword(s):

Research Funding ◽

Tp53 Mutation ◽

Continuous Variable ◽

Lymphocytic Leukemia ◽

Genotype Data ◽

Mdm2 Snp309 ◽

Expression Levels ◽

Significant Difference ◽

Complete Disruption ◽

Previously Treated

Abstract Abstract 3521 MicroRNA-34a (miR-34a), a direct downstream target of the tumor suppressor TP53 is upregulated in chronic lymphocytic leukemia (CLL) cells and leads to apoptosis and cell cycle arrest. Previous studies found low miR-34a expression levels in CLL patients with TP53 gene disruptions by either 17p13 deletions or TP53 mutations and this has been linked to chemotherapy resistance and poor prognosis. Alternatively, miR-34a expression levels might be influenced by a single nucleotide polymorphism 309 (SNP 309) in the intronic MDM2 promoter. In this work we retrospectively determined miR-34a expression levels and the TP53 status in previously treated CLL samples enrolled in an international phase III clinical study comparing Fludarabine and Cyclophosphamide with or without Rituximab (FC versus R-FC: REACH trial). MicroRNA profiling data (Affymetrix GeneChip miRNA 1.0 array) and TP53 mutation data (AmpliChip p53 Test and Sanger sequencing) were available for 275 of 546 patients at treatment begin. In this subgroup of patients, genotype data (Illumina 550k HumanHap array) were available for 265 of 275 patients. A Mann-Whitney Wilcoxon test was used to compare distributions across two groups for a continuous variable. Association of the clinical data with progression-free survival (PFS) was assessed by Cox proportional hazard models. Patients were stratified into the following three groups: patients with both a 17p13 deletion and a TP53 mutation and patients with known dominant negative mutations of TP53 (n=21) (complete disruption of TP53), patients with either a 17p13 deletion (n=8) or a TP53 mutation (n=10) (partial disruption of TP53), and patients without TP53 aberrations (n=236) (wildtype TP53 and no 17p13 deletion). The distribution of miR-34a expression levels (log2 transformed) was compared across these groups. Patients with a complete disruption of TP53 function (mean=2.1, sd=2.1) had significantly lower miR-34a expression levels compared to patients without TP53 aberrations (mean=6.8, sd=2.3, p <0.001). Very interestingly, patients with a complete disruption of TP53 function also had lower miR-34a expression levels compared to patients with partial loss of TP53 function either by TP53 mutation (mean=7.1, sd=2.3, p <0.001) or deletion of the 17p13 locus (mean=7.2, sd=1.5, p <0.001). Patients with partial loss of TP53 function showed relatively high expression levels of miR-34a and no significant difference in miR-34a expression levels in patients without TP53 aberrations. There was a high variability of miR-34a expression levels in the group of patients without TP53 aberrations, with several patients having a low miR-34a. In order to find out whether this variability could be explained in part by SNP309 in the MDM2 promoter, we stratified patients without TP53 aberrations and with available genotype data (n=208) according to the genotype for SNP309. Because SNP309 was not on the Illumina chip, we imputed its genotype by using a perfect proxy (SNP rs2279744, r-square=1.0 with SNP309, according to public Caucasian Hapmap genotype data). We then compared the miR-34a expression levels between groups defined by the SNP309GG genotype (n=28, mean=7.5, sd=2.1), the heterozygous GT variant (n=101, mean=6.9, sd=2.2) and the wildtype TT-genotype (n=79, mean=6.6, sd=2.5). We could not observe any significant difference in miR-34a expression levels associated with the SNP309 genotype. A multivariate survival analysis was then used to further assess whether miR-34a expression levels in the group of patients without TP53 aberrations was of prognostic relevance with regards to PFS. MiR-34a expression did not predict PFS in patients without TP53 aberrations, neither as a continuous variable (HR: 1.03 (0.95–1.1), p =0.5) nor as a binary variable (dichotomized by its median value: HR: 0.92 (0.7–1.3), p =0.6) after adjustment for treatment, age, Binet stage and IGVH mutational status. In previously treated CLL patients, only a complete loss of TP53 function correlates with low miR-34a expression levels. MiR-34a expression levels did not demonstrate prognostic significance in CLL patients without TP53 mutations and did not correlate with the presence or absence of MDM2 SNP309. Further studies are warranted to assess the functional and clinical role of miR-34a expression as prognostic factor in patients with a disruption of TP53 function. Disclosures: Dufour: Roche: Research Funding. Bohlander:Roche: Research Funding. Spiekermann:Roche: Research Funding. Schneider:Roche: Research Funding. Hiddemann:Roche: Research Funding. Truong:Roche: Employment. Patten:Roche: Employment. Wu:Roche: Employment. Dmoszynska:Roche: Honoraria. Robak:Centocor Ortho Biotech Research & Development: Research Funding. Geisler:Roche: Speakers Bureau. Dornan:Genentech: Employment. Lin:Genentech: Employment. Yeh:Genentech: Employment. Weisser:Roche: Employment. Duchateau-Nguyen:Roche: Employment. Palermo:Roche: Employment.

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Correlation of tumor mutational burden (TMB) with CDKN2A and TP53 mutation in HPV-negative head and neck squamous cell carcinoma (HNSCC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6552 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6552-6552 ◽

Cited By ~ 1

Author(s):

Barbara Burtness ◽

Alexander Deneka ◽

Yasmine Baca ◽

Ilya Serebriiskii ◽

Mitchell I. Parker ◽

...

Keyword(s):

Oral Cavity ◽

Tp53 Mutation ◽

Predictive Biomarker ◽

Dominant Negative ◽

Alternative Methods ◽

Missense Mutations ◽

Loss Of Function ◽

Tp53 Mutations ◽

Cdkn2a Mutation ◽

Mutational Status

6552 Background: The tumor suppressors TP53 and CDKN2A are commonly mutated or lost in HNSCC, impairing G1 checkpoints. This reduces ability to repair DNA damage arising from hypoxia, replication stress, and mutagen exposure, thus increasing TMB, a potential predictive biomarker for immunotherapy benefit. TP53 mutations can be classified as loss-of-function (LOF) with or without dominant negative (DNE) activity, gain-of-function (GOF) and benign. We investigated whether specific categories of TP53 mutation were associated with increased TMB, and whether these cooperated with CDKN2A mutation to elevate TMB. Methods: We analyzed 1010 HPV- HNSCC tumor samples (246 female) profiled with a 592-gene panel by Caris Life Sciences from 2015 to 2019. Predominant subsites were oral cavity (285), oropharynx (225) and larynx (153). TMB reflected all somatic nonsynonymous missense mutations detected. We report mean TMB per megabase (MB). Pathogenicity of TP53 and CDKN2A mutations was determined according to American College of Medical Genetics (ACMG) guidelines. We also used four alternative methods of characterizing TP53 mutations based on analysis of protein structure, public databases (IARC, ClinVar, InterVar), and publications (PMID: 25108461 and others) assessing structure-function relations. Results: 60% of cases had TP53 mutations ( TP53mut) designated pathogenic by ACMG guidelines. Estimates of frequency of LOF/DNE mutations ranged from 30-42.8% of cases among the alternative classification methods. Damaging CDKN2A mutations were present in 20%. Average TMB per MB varied from 8.2/8.6 (females/males) in oral cavity cancers to 26.5/27.7 (females/males) in cancer of the lip. Mean TMB was typically higher in the presence of damaging LOF/DNE TP53 mutations or CDKN2A mutations, but not TP53 GOF mutations. Based on ACMG, for tumors with TP53 and CDKN2A wild type (WT) TMB was 8.03, for those with CDKN2Amut-only 9.82, for TP53mut-only 10.56, and TP53 mut/CDKN2A mut 17.6 (p < 0.001). For disruptive TP53mut (Poeta algorithm), mean TMB for WT/WT was 8.67, for TP53mut 11.31, CDKN2Amut 17.9 and TP53mut/CDKN2A mut 15.83 (p < 0.001). Conclusions: Mutation of TP53 and/or CDKN2A is associated with increased mean TMB relative to WT; mean TMB was highest for tumors bearing damaging mutations in both genes. GOF TP53 mutation was not clearly associated with increased TMB. As TMB is evaluated as a predictive biomarker in the immunotherapy of HNSCC, specific TP53/CDKN2A mutational status should also be evaluated.

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Evaluation of the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) in Elderly Patients with Comorbidities: Analysis of the CLL11 Study Population

Blood ◽

10.1182/blood.v128.22.4401.4401 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4401-4401 ◽

Cited By ~ 6

Author(s):

Valentin Goede ◽

Jasmin Bahlo ◽

Nadine Kutsch ◽

Kirsten Fischer ◽

Anna Maria Fink ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Research Funding ◽

Tp53 Mutation ◽

Risk Groups ◽

Lymphocytic Leukemia ◽

Intermediate Risk ◽

Mutational Status ◽

Very High ◽

Support Research

Abstract Introduction: There are a growing number of therapeutic options for elderly patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, thus making clinical aids necessary to choose between available treatments. CLL-IPI is a validated tool for prognostication of overall survival in CLL (with age, stage, beta2-microglobulin, 17p deletion / TP53 mutation, and IGHV mutational status used as weighted factors to stratify patients for low, intermediate, high, or very high risk of death). We here evaluated CLL-IPI in a large sample of elderly patients with comorbidities. Methods: CLL-IPI was analyzed in the population of the CLL11 study, a randomized trial having enrolled 781 patients with previously untreated CLL and increased comorbidity burden for treatment with obinutuzumab (formerly GA101) plus chlorambucil (G-Clb, n=333), rituximab plus chlorambucil (R-Clb, n=330), or chlorambucil alone (Clb, n=118). Patients with all five CLL-IPI factors available were stratified into CLL-IPI risk groups. Overall survival (OS) was estimated for low, intermediate, high, and very high risk. Additionally, risk-specific time to next treatment (TTNT) and progression-free survival (PFS) were assessed. Methods included Kaplan-Meier curve, log-rank test, and Cox regression analyses. Results: Among 781 patients enrolled in the CLL11 study, 691 were evaluable in this analysis while 90 had to be excluded due to missing information for beta2-microglobulin, 17p deletion / TP53 mutation, or IGHV mutational status. Of the 691 patients, 299 were treated with G-Clb, 294 with R-Clb, and 98 with Clb. Median age, cumulative illness rating scale (CIRS), and ECOG performance status were 74 years, 8 and 1, respectively. Median observation time was 41.8 months. Stratification according to CLL-IPI was as follows: 62 (9%) low risk, 206 (30%) intermediate risk, 361 (52%) high risk, 62 (9%) very high risk. In a pooled analysis of all 691 evaluable patients, OS was significantly different between CLL-IPI risk groups (p<0.001, Figure), with statistically satisfying values regarding both discrimination and calibration (C-statistics: C=0.633, 95%-CI 0.596-0.676; Hosmer-Lemeshow-Test: p=0.716). Similarly, graduating differences in OS between CLL-IPI risk groups were found in the subset of patients treated with chemoimmunotherapy and subsets of patients of each antibody arm, respectively. TTNT and PFS also differed between CLL-IPI risk groups. Favorable risk as assessed by CLL-IPI was associated with greater likelihood of OS benefit from treatment with G-Clb versus R-Clb (HR 0.232, 95%-CI, 0.027-1.983 for low risk; HR 0.540, 95%-CI 0.249-1.170 for intermediate risk; HR 0.884, 95%-CI 0.595-1.315 for high risk; HR 0.830, 95%-CI 0.372-1.852 for very high risk). Previously observed TTNT and PFS benefits from G-Clb versus R-Clb were maintained across CLL-IPI risk groups. Conclusions: This is the first validation study of CLL-IPI in elderly patients with previously untreated CLL in need of therapy and comorbidities. Results suggest good performance of the CLL-IPI in this patient population. CLL-IPI may provide help to physicians to choose between available treatment options in these patients. Figure OS by CLL-IPI risk groups in the analyzed CLL11 study sample (n=691) Figure. OS by CLL-IPI risk groups in the analyzed CLL11 study sample (n=691) Disclosures Goede: F- Hoffmann-LaRoche: Consultancy, Honoraria, Other: Travel grants; Gilead: Consultancy; Janssen: Consultancy, Other: Travel grants; Glaxo Smith Kline: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Bristol Myer Squibb: Honoraria. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Fischer:Roche: Other: travel grants. Fink:Mundipharma: Other: Travel grants; AbbVie: Other: Travel grants; Roche: Honoraria, Other: Travel grants; Celgene: Research Funding. Fingerle-Rowson:Roche: Employment. Stilgenbauer:Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genzyme: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding. Bergmann:Janssen: Honoraria; Gilead: Consultancy, Honoraria; Glaxo-SmithKline: Honoraria; Celgene: Honoraria; Roche: Consultancy, Honoraria; Mundipharma: Honoraria. Eichhorst:Mundipharma: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Hallek:F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

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Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up

Blood ◽

10.1182/blood-2008-04-154070 ◽

2008 ◽

Vol 112 (8) ◽

pp. 3322-3329 ◽

Cited By ~ 272

Author(s):

Thorsten Zenz ◽

Alexander Kröber ◽

Katrin Scherer ◽

Sonja Häbe ◽

Andreas Bühler ◽

...

Keyword(s):

Tp53 Mutation ◽

Direct Sequencing ◽

Clonal Evolution ◽

Lymphocytic Leukemia ◽

Prognostic Impact ◽

Clone Size ◽

Tp53 Mutations ◽

Long Term Follow Up ◽

Serial Samples

AbstractThe exact prognostic role of TP53 mutations (without 17p deletion) and any impact of the deletion without TP53 mutation in CLL are unclear. We studied 126 well-characterized CLL patients by direct sequencing and DHPLC to detect TP53 mutations (exons 2-11). Most patients with 17p deletions also had TP53 mutations (81%). Mutations in the absence of 17p deletions were found in 4.5%. We found a shorter survival for patients with TP53 mutation (n = 18; P = .002), which was more pronounced when analyzed from the time point of mutation detection (6.8 vs 69 months, P < .001). The survival was equally poor for patients with deletion 17p plus TP53 mutation (7.6 months, n = 13), TP53 mutation only (5.5 months, n = 5), and 17p deletion only (5.4 months, n = 3). The prognostic impact of TP53 mutation (HR 3.71) was shown to be independent of stage, VH status, and 11q and 17p deletion in multivariate analysis. Serial samples showed evidence of clonal evolution and increasing clone size during chemotherapy, suggesting that there may be patients where this treatment is potentially harmful. TP53 mutations are associated with poor sur-vival once they occur in CLL. The de-monstration of clonal evolution under selective pressure supports the biologic significance of TP53 mutations in CLL.

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