Genomic complexity and IGHV mutational status are key predictors of outcome of chronic lymphocytic leukemia patients with TP53 disruption.
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ABSTRACT:
SUBMITTER: Delgado J
PROVIDER: S-EPMC4222465 | biostudies-literature | 2014 Nov
REPOSITORIES: biostudies-literature
Publications
Genomic complexity and IGHV mutational status are key predictors of outcome of chronic lymphocytic leukemia patients with TP53 disruption.
Delgado Julio J Salaverria Itziar I Baumann Tycho T Martínez-Trillos Alejandra A Lee Eriong E Jiménez Laura L Navarro Alba A Royo Cristina C Santacruz Rodrigo R López Cristina C Payer Angel R AR Colado Enrique E González Marcos M Armengol Lluís L Colomer Dolors D Pinyol Magda M Villamor Neus N Aymerich Marta M Carrió Ana A Costa Dolors D Clot Guillem G Giné Eva E López-Guillermo Armando A Campo Elías E Beà Sílvia S
Haematologica 20140704 11
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Project description:Patients with chronic lymphocytic leukemia and unmutated immunoglobulin heavy-chain variable region gene (IGHV) have inferior survival from time of treatment in clinical studies. We assessed real-world outcomes based on mutational status and treatment regimen in a nationwide population-based cohort, comprising all 4,135 patients from the Danish chronic lymphocytic leukemia registry diagnosed between 2008 and 2017. In total, 850 patients with known mutational status received treatment: 42% of patients received intensive chemoimmunotherapy consisting of fludarabine, cyclophosphamide plus rituximab, or bendamustine plus rituximab; 27% received chlorambucil in combination with anti-CD20 antibodies or as monotherapy, and 31% received other, less common treatments. No difference in overall survival from time of first treatment according to mutational status was observed, while treatment-free survival from start of first treatment was inferior for patients with unmutated IGHV. The median treatment-free survival was 2.5 years for patients treated with chlorambucil plus anti-CD20, and 1 year for those who received chlorambucil monotherapy. The 3-year treatment-free survival rates for patients treated with fludarabine, cyclophosphamide plus rituximab, and bendamustine plus rituximab were 90% and 91% for those with mutated IGHV, and 76% and 53% for those with unmutated IGHV, respectively, and the 3-year overall survival rates were similar for the two regimens (86-88%). Thus, it appears that, in the real-world setting, patients progressing after intensive chemoimmunotherapy as first-line therapy can be rescued by subsequent treatment, without jeopardizing their long overall survival. Intensive chemoimmunotherapy remains a legitimate option alongside targeted agents, and part of a personalized treatment landscape in chronic lymphocytic leukemia, while improved supportive care and treatment options are warranted for unfit patients.
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Project description:In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents.
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Project description:We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases. A complex karyotype was present in 21 patients. Mutations were detected in 56 cases and were associated with unmutated IGHV status (p = 0.040) and complex karyotype (p = 0.047). TP53 disruption (i.e. TP53 mutations and/or 17p13 deletion by FISH) correlated with the presence of ≥ 2 mutations (p = 0.001) and a complex karyotype (p = 0.012). By multivariate analysis, an advanced Binet stage (p < 0.001) and an unfavorable karyotype (p = 0.001) predicted a shorter time to first treatment. TP53 disruption (p = 0.019) and the unfavorable karyotype (p = 0.028) predicted a worse overall survival. A shorter time to chemorefractoriness was associated with TP53 disruption (p = 0.001) and unfavorable karyotype (p = 0.025). Patients with both unfavorable karyotype and TP53 disruption presented a dismal outcome (median overall survival and time to chemorefractoriness of 28.7 and 15.0 months, respectively). In conclusion, karyotype analysis refines risk stratification in high-risk CLL patients and could identify a subset of patients with highly unfavorable outcome requiring alternative treatments.
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Project description:Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.
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Project description:NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact of NOTCH1 mutations on clinical course of CLL has been widely studied, the prognostic role of NOTCH1 activation in CLL remains to be defined. Here, we analyzed the activation of NOTCH1/NOTCH2 (ICN1/ICN2) and the expression of JAGGED1 (JAG1) in 163 CLL patients and evaluated their impact on TTFT (Time To First Treatment) and OS (Overall Survival). NOTCH1 activation (ICN1+) was found in 120/163 (73.6%) patients. Among them, 63 (52.5%) were NOTCH1 mutated (ICN1+/mutated) and 57 (47.5%) were NOTCH1 wild type (ICN1+/WT). ICN1+ patients had a significant reduction of TTFT compared to ICN1-negative (ICN1-). In the absence of NOTCH1 mutations, we found that the ICN1+/WT group had a significantly reduced TTFT compared to ICN1- patients. The analysis of IGHV mutational status showed that the distribution of the mutated/unmutated IGHV pattern was similar in ICN1+/WT and ICN1- patients. Additionally, TTFT was significantly reduced in ICN1+/ICN2+ and ICN1+/JAG1+ patients compared to ICN1-/ICN2- and ICN1-/JAG1- groups. Our data revealed for the first time that NOTCH1 activation is a negative prognosticator in CLL and is not correlated to NOTCH1 and IGHV mutational status. Activation of NOTCH2 and JAGGED1 expression might also influence clinical outcomes in this group, indicating the need for further dedicated studies. The evaluation of different NOTCH network components might represent a new approach to refine CLL risk stratification.
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Project description:BackgroundPrognostic index for survival estimation by clinical-demographic variables were previously proposed in chronic lymphocytic leukemia (CLL) patients. Our objective was to test in a large retrospective cohort of CLL patients the prognostic power of biological and clinical-demographic variable in a comprehensive multivariate model. A new prognostic index was proposed.MethodsOverall survival and time to treatment in 620 untreated CLL patients were analyzed retrospectively to evaluate the multivariate independence and predictive power of mutational status of immunoglobulin heavy chain variable gene segments (IGHV), high-risk chromosomal aberration such as 17p or 11q deletions, CD38 and ZAP-70 expression, age, gender, Binet stage, β2-microglobulin levels, absolute lymphocyte count and number of lymph node regions.ResultsIGHV mutational status and 17p deletion were the sole biological variables with independent prognostic relevance in a multivariate model for overall survival, which included easily measurable clinical parameters (Binet staging, β2-microglobulin levels) and demographics (age and gender). Analysis of time to treatment in Binet A patients below 70 years of age showed that IGHV was the most important predictor. A novel 6-variable clinical-biological prognostic index was developed and internally validated, which assigned 3 points for Binet C stage, 2 points/each for Binet B stage and for age > 65 years, 1 point/each for male gender, high β2-microglobulin levels, presence of an unmutated IGHV gene status or 17p deletion. Patients were classified at low-risk (score = 0-1; 21%), intermediate-risk (score 2-5; 63% of cases), high-risk (score 6-9; 16% of cases). Projected 5-year overall survival was 98%, 90% and 58% in low-, intermediate- and high-risk groups, respectively. A nomogram for individual patient survival estimation was also proposed.ConclusionsData indicate that IGHV mutational status and 17p deletion may be integrated with clinical-demographic variables in new prognostic tools to estimate overall survival.
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Project description:Chemoimmunotherapy with combined fludarabine, cyclophosphamide and rituximab (FCR) has been an effective treatment for patients with chronic lymphocytic leukemia (CLL). We initiated a phase II trial for previously untreated patients with CLL with mutated IGHV and absence of del(17p)/TP53 mutation. Patients received ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for three cycles. Patients who achieved complete remission (CR)/CR with incomplete count recvoery (CRi) with marrow undetectable measurable residual disease (U-MRD) received additional nine cycles of ibrutinib with three cycles of obinutuzumab; all others received nine additional cycles of ibrutinib and obinutuzumab. Patients in marrow U-MRD remission after cycle 12 discontinued all treatment, including ibrutinib. Forty-five patients were treated. The median follow-up is 41.3 months. Among the total 45 treated patients, after three cycles, 38% achieved CR/CRi and 87% achieved marrow U-MRD. After cycle 12, the corresponding numbers were 67% and 91%, respectively. Overall, 44/45 (98%) patients achieved marrow U-MRD as best response. No patient had CLL progression. The 3-year progression-free survival (PFS) and overall survival (OS) were 98% and 98%, respectively. Per trial design, all patients who completed cycle 12 discontinued ibrutinib, providing for a time-limited therapy. Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% patients, respectively. The iFCG regimen with only 3 cycles of chemotherapy is an effective, time-limited regimen for patients with CLL with mutated IGHV and without del(17p)/TP53 mutation.
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Project description:Genome studies of chronic lymphocytic leukemia (CLL) have revealed the remarkable subclonal heterogeneity of the tumors, but the clinical implications of this phenomenon are not well known. We assessed the mutational status of 28 CLL driver genes by deep-targeted next-generation sequencing and copy number alterations (CNA) in 406 previously untreated patients and 48 sequential samples. We detected small subclonal mutations (0.6-25% of cells) in nearly all genes (26/28), and they were the sole alteration in 22% of the mutated cases. CNA tended to be acquired early in the evolution of the disease and remained stable, whereas the mutational heterogeneity increased in a subset of tumors. The prognostic impact of different genes was related to the size of the mutated clone. Combining mutations and CNA, we observed that the accumulation of driver alterations (mutational complexity) gradually shortened the time to first treatment independently of the clonal architecture, IGHV status and Binet stage. Conversely, the overall survival was associated with the increasing subclonal diversity of the tumors but it was related to the age of patients, IGHV and TP53 status of the tumors. In conclusion, our study reveals that both the mutational complexity and subclonal diversity influence the evolution of CLL.
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Project description:The mutational status of immunoglobulin (IG) light chain genes in chronic lymphocytic leukemia (CLL) and its clinical impact have not been extensively studied. To assess their prognostic significance, the IG light chain gene repertoire in CLL patients has been evaluated using a training-validation approach. In the training cohort (N = 573 CLL), 92.5% showed productive IG light chain genes rearrangements, with IGKV4-1 (20.5%) and IGLV3-21 (19.0%) being the most common. A 99.0% somatic hypermutation cut-off was identified as the best predictor for time to first treatment (TTFT) in 414 Binet A CLL patients of the training cohort. Patients with unmutated (UM) light chain genes displayed a 10-year treatment free probability of 32.4% versus 73.2% for those with mutated (M) genes (p < 0.0001). Importantly, UM light chain genes maintained an independent association with a shorter TTFT when adjusted for the IPS-E prognostic model variables, that also includes IGHV mutational status. The validation cohort of 343 Rai 0 patients confirmed these findings, with UM light chain genes predicting a 7-year treatment free probability of 42.0% versus 73.7% for M genes (p < 0.0001). These results indicate that the mutational status of the light chain genes is an independent predictor of shorter TTFT in early-stage CLL patients.
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