ABSTRACT
Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma associated with MYC translocation. Here, we describe drug response profiling of 42 blood cancer cell lines including 17 BL to 32 drugs targeting key cancer pathways and provide a systematic study of drug combinations in BL cell lines. Based on drug response, we identified cell line specific sensitivities, i.e. to venetoclax driven by BCL2 overexpression and partitioned subsets of BL driven by response to kinase inhibitors. In the combination screen, including BET, BTK and PI3K inhibitors, we identified synergistic combinations of PI3K and BTK inhibition with drugs targeting Akt, mTOR, BET and doxorubicin. A detailed comparison of PI3K and BTKi combinations identified subtle differences, in line with convergent pathway activity. Most synergistic combinations were identified for the BET inhibitor OTX015, which showed synergistic effects for 41% of combinations including inhibitors of PI3K/AKT/mTOR signalling. The strongest synergy was observed for the combination of the CDK 2/7/9 inhibitor SNS032 and OTX015. Our data provide a landscape of drug combination effects in BL and suggest that targeting CDK and BET could provide a novel vulnerability of BL.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Burkitt Lymphoma/drug therapy , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Acetanilides/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Burkitt Lymphoma/pathology , Cell Line, Tumor , Drug Combinations , Drug Synergism , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Oxazoles/pharmacology , Sulfonamides/pharmacology , Thiazoles/pharmacologyABSTRACT
In chronic lymphocytic leukemia (CLL), TP53 gene defects, due to deletion of the 17p13 locus and/or mutation(s) within the TP53 gene, are associated with resistance to chemoimmunotherapy and a particularly dismal clinical outcome. On these grounds, analysis of TP53 aberrations has been incorporated into routine clinical diagnostics to improve patient stratification and optimize therapeutic decisions. The predictive implications of TP53 aberrations have increasing significance in the era of novel targeted therapies, i.e., inhibitors of B-cell receptor (BcR) signaling and anti-apoptotic BCL2 family members, owing to their efficacy in patients with TP53 defects. In this report, the TP53 Network of the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) presents updated recommendations on the methodological approaches for TP53 mutation analysis. Moreover, it provides guidance to ensure that the analysis is performed in a timely manner for all patients requiring treatment and that the data is interpreted and reported in a consistent, standardized, and accurate way. Since next-generation sequencing technologies are gaining prominence within diagnostic laboratories, this report also offers advice and recommendations for the interpretation of TP53 mutation data generated by this methodology.
Subject(s)
DNA Mutational Analysis/methods , Genes, p53/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Europe , High-Throughput Nucleotide Sequencing/methods , HumansABSTRACT
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.
Subject(s)
Antineoplastic Agents/pharmacology , Biomarkers, Tumor , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , High-Throughput Screening Assays , Leukemia, Prolymphocytic, T-Cell/genetics , Mutation , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Cell Cycle/genetics , Cell Line, Tumor , Chromosome Aberrations , Female , Gene Expression , Gene Expression Profiling , Humans , Janus Kinases/metabolism , Leukemia, Prolymphocytic, T-Cell/drug therapy , Leukemia, Prolymphocytic, T-Cell/metabolism , Male , Middle Aged , Molecular Targeted Therapy , Oxazoles/pharmacology , Phenotype , Protein Kinase Inhibitors/pharmacology , STAT Transcription Factors/metabolism , Thiazoles/pharmacologyABSTRACT
Chronic lymphocytic leukemias (CLLs) with unmutated (U-CLL) or mutated (M-CLL) IGHV have variable features of immunosuppression, possibly influenced by those CLL cells activated to produce interleukin 10 (IL-10). The two subsets differ in their levels of anergy, defined by low surface immunoglobulin M levels/signaling capacity, and in their DNA methylation profile, particularly variable in M-CLL. We have now found that levels of IL-10 produced by activated CLL cells were highly variable. Levels were higher in M-CLL than in U-CLL and correlated with anergy. DNA methylation analysis of IL10 locus revealed two previously uncharacterized 'variably methylated regions' (CLL-VMRs1/2) in the gene body, but similarly low methylation in the promoter of both U-CLL and M-CLL. CLL-VMR1/2 methylation was lower in M-CLL than in U-CLL and inversely correlated with IL-10 induction. A functional signal transducer and activator of transcription 3 (STAT3) binding site in CLL-VMR2 was confirmed by proximity ligation and luciferase assays, whereas inhibition of SYK-mediated STAT3 activation resulted in suppression of IL10. The data suggest epigenetic control of IL-10 production. Higher tumor load may compensate the reduced IL-10 production in U-CLL, accounting for clinical immunosuppression in both subsets. The observation that SYK inhibition also suppresses IL-10 provides a potential new rationale for therapeutic targeting and immunological rescue by SYK inhibitors in CLL.
Subject(s)
DNA Methylation , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Interleukin-10/biosynthesis , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Mutation , Humans , Interleukin-10/genetics , STAT3 Transcription Factor/metabolism , Syk Kinase/antagonists & inhibitors , Syk Kinase/physiologyABSTRACT
Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.
Subject(s)
Early Growth Response Protein 2/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Adult , Aged , Female , Genes, p53 , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/classification , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Proportional Hazards ModelsABSTRACT
The ATM-p53 DNA-damage response (DDR) pathway has a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53 and ATM. Identifying and distinguishing TP53 and ATM functional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as the underlying cause of chemoresistance. Also, specific treatments sensitizing TP53- or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53 versus ATM and (iii) enable the identification of additional defects in the ATM-p53 pathway. Reversed transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was used to measure ATM and/or p53-dependent genes at the RNA level following DNA damage using irradiation. Here, we showed that this assay is able to identify and distinguish three subgroups of CLL tumors (i.e., TP53-defective, ATM-defective and WT) and is also able to detect additional samples with a defective DDR, without molecular aberrations in TP53 and/or ATM. These findings make the ATM-p53 RT-MLPA functional assay a promising prognostic tool for predicting treatment responses in CLL.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/genetics , Gene Expression Regulation, Leukemic , Multiplex Polymerase Chain Reaction/methods , Mutation , Reverse Transcriptase Polymerase Chain Reaction/methods , Tumor Suppressor Protein p53/genetics , Antineoplastic Agents/pharmacology , Ataxia Telangiectasia Mutated Proteins/metabolism , Biological Assay , DNA Damage , Doxorubicin/pharmacology , Drug Resistance, Neoplasm/genetics , Epigenesis, Genetic , Gamma Rays , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , RNA, Neoplasm/genetics , Sensitivity and Specificity , Tumor Suppressor Protein p53/metabolism , Vidarabine/analogs & derivatives , Vidarabine/pharmacologyABSTRACT
To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Adult , Aged , Disease Eradication , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Recurrence , Retrospective Studies , Treatment OutcomeABSTRACT
Mutations of the tumor suppressor p53 lead to chemotherapy resistance and a dismal prognosis in chronic lymphocytic leukemia (CLL). Whereas p53 targets are used to identify patient subgroups with impaired p53 function, a comprehensive assessment of non-coding RNA targets of p53 in CLL is missing. We exploited the impaired transcriptional activity of mutant p53 to map out p53 targets in CLL by small RNA sequencing. We describe the landscape of p53-dependent microRNA/non-coding RNA induced in response to DNA damage in CLL. Besides the key p53 target miR-34a, we identify a set of p53-dependent microRNAs (miRNAs; miR-182-5p, miR-7-5p and miR-320c/d). In addition to miRNAs, the long non-coding RNAs (lncRNAs) nuclear enriched abundant transcript 1 (NEAT1) and long intergenic non-coding RNA p21 (lincRNA-p21) are induced in response to DNA damage in the presence of functional p53 but not in CLL with p53 mutation. Induction of NEAT1 and lincRNA-p21 are closely correlated to the induction of cell death after DNA damage. We used isogenic lymphoma cell line models to prove p53 dependence of NEAT1 and lincRNA-p21. The current work describes the p53-dependent miRNome and identifies lncRNAs NEAT1 and lincRNA-p21 as novel elements of the p53-dependent DNA damage response machinery in CLL and lymphoma.
Subject(s)
Apoptosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , Tumor Suppressor Protein p53/genetics , Aged , Aged, 80 and over , Blotting, Western , Cell Proliferation , Chromatin Immunoprecipitation , DNA Damage , Female , Flow Cytometry , Humans , Male , Middle Aged , Neoplasm Staging , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolismABSTRACT
Hairy cell leukemia was initially described as a distinct entity in 1958. It is rare B-cell malignancy characterized by an indolent course. Advances in the treatment and understanding of the biology of hairy cell leukemia have made the disease exquisitely amenable to treatment. This review summarizes the present understanding of hairy cell leukemia with a particular focus on the development of novel and targeted approaches to treatment.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Genetic Markers/genetics , Leukemia, Hairy Cell/diagnosis , Leukemia, Hairy Cell/therapy , Molecular Targeted Therapy/methods , Genetic Predisposition to Disease/genetics , Humans , Leukemia, Hairy Cell/geneticsABSTRACT
Mutations or deletions in TP53 or ATM are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with ATM aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (n=110) containing ATM, SF3B1 and TP53 gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly, SF3B1 mutated samples without concurrent ATM and TP53 aberrations (sole SF3B1) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast, NOTCH1 or K/N-RAS mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole SF3B1 mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with SF3B1 mutations.
Subject(s)
Gene Expression Regulation, Leukemic , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Phosphoproteins/genetics , Ribonucleoprotein, U2 Small Nuclear/genetics , Apoptosis , Ataxia Telangiectasia Mutated Proteins/metabolism , Cohort Studies , DNA Damage , DNA Mutational Analysis , Doxorubicin/pharmacology , Flow Cytometry , Gene Deletion , Genome, Human , Histones/metabolism , Humans , Imidazoles/pharmacology , Piperazines/pharmacology , Prognosis , RNA Splicing Factors , Receptor, Notch1/genetics , Tumor Suppressor Protein p53/genetics , Vidarabine/analogs & derivatives , Vidarabine/pharmacologyABSTRACT
BACKGROUND: In a single-center retrospective donor versus no-donor comparison, we investigated if allogeneic stem cell transplantation (alloSCT) can improve the dismal course of poor-risk chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: All patients with CLL who were referred for evaluation of alloSCT within a 7-year time frame and had a donor search indication according to the EBMT criteria or because of Richter's transformation were included. Patients for whom a matched donor could be found within 3 months (matches) were compared with patients without such a donor (controls). Primary end point was overall survival measured from the 3-month landmark after search initiation. RESULTS: Of 105 patients with donor search, 97 (matches 83; controls 14) were assessable at the 3-month landmark. Matches and controls were comparable for age, gender, time from diagnosis, number of previous regimens, and remission status. Disregarding if alloSCT was actually carried out or not, survival from the 3-month landmark was significantly better in matches versus controls [hazard ratio 0.38, 95% confidence interval (CI) 0.17-0.85; P = 0.014]. The survival benefit of matches remained significant on multivariate analysis. CONCLUSION: This study provides first comparative evidence that alloSCT may have the potential to improve the natural course of poor-risk CLL as defined by the EBMT criteria.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Stem Cell Transplantation , Adult , Aged , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Multivariate Analysis , Proportional Hazards Models , Retrospective Studies , Risk , Tissue Donors , Transplantation, Homologous , Treatment OutcomeABSTRACT
Chronic lymphocytic leukemia (CLL) is an incurable malignancy of mature B cells. One of the major challenges in treatment of CLL is the achievement of a complete remission to prevent relapse of disease originating from cells within lymphoid tissues and subsequent chemoresistance. In search for novel drugs that target CLL cells in protective microenvironments, we performed a fungal extract screen using cocultures of primary CLL cells with bone marrow-derived stromal cells. A secondary metabolite produced by Penicillium aquamarinium was identified as Chaetoglobosin A (ChA), a member of the cytochalasan family that showed preferential induction of apoptosis in CLL cells, even under culture conditions that mimic lymphoid tissues. In vitro testing of 89 CLL cases revealed effective targeting of CLL cells by ChA, independent of bad prognosis characteristics, like 17p deletion or TP53 mutation. To provide insight into its mechanism of action, we showed that ChA targets filamentous actin in CLL cells and thereby induces cell-cycle arrest and inhibits membrane ruffling and cell migration. Our data further revealed that ChA prevents CLL cell activation and sensitizes them for treatment with PI3K and BTK inhibitors, suggesting this compound as a novel potential drug for CLL.
Subject(s)
Apoptosis/drug effects , Cytokinesis/drug effects , Cytoskeleton/drug effects , Indole Alkaloids/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Mycotoxins/pharmacology , Stromal Cells/drug effects , Actins/metabolism , Blotting, Western , Case-Control Studies , Cell Adhesion/drug effects , Cell Cycle/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Coculture Techniques , Cytoskeleton/metabolism , Flow Cytometry , Fungi/chemistry , Healthy Volunteers , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Stromal Cells/metabolism , Stromal Cells/pathology , Tumor Cells, CulturedSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Cyclophosphamide/administration & dosage , Disease Progression , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Male , Middle Aged , Prognosis , Rituximab , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/analogs & derivativesABSTRACT
Recently, the p53-miR-34a network has been identified to have an important role in tumorigenesis. As in acute myeloid leukemia with complex karyotype (CK-AML) TP53 alterations are the most common known molecular lesion, we further analyzed the p53-miR-34a axis in a large cohort of CK-AML with known TP53 status (TP53(altered), n=57; TP53(unaltered), n=31; altered indicates loss and/or mutation of TP53). Profiling microRNA (miRNA) expression delineated TP53 alteration-associated miRNA profiles, and identified miR-34a and miR-100 as the most significantly down- and upregulated miRNA, respectively. Moreover, we found a distinct miR-34a expression-linked gene expression profile enriched for genes belonging to p53-associated pathways, and implicated in cell cycle progression or apoptosis. Clinically, low miR-34a expression and TP53 alterations predicted for chemotherapy resistance and inferior outcome. Notably, in TP53(unaltered) CK-AML, high miR-34a expression predicted for inferior overall survival (OS), whereas in TP53(biallelic altered) CK-AML, high miR-34a expression pointed to better OS. Thus, detailed molecular profiling links impaired p53 to decreased miR-34a expression, but also identifies p53-independent miR-34a induction mechanisms as shown in TP53(biallelic altered) cell lines treated with 15-deoxy-Δ(12,14)-prostaglandin. An improved understanding of this mechanism might provide novel therapeutic options to restore miR-34a function and thereby induce cell cycle arrest and apoptosis in TP53(altered) CK-AML.
Subject(s)
Biomarkers, Tumor/genetics , Chromosome Aberrations , Leukemia, Myeloid, Acute/genetics , MicroRNAs/genetics , Tumor Suppressor Protein p53/genetics , Adolescent , Adult , Aged , Cells, Cultured , Female , Gene Expression Profiling , Humans , Karyotyping , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Young AdultABSTRACT
Chronic lymphocytic leukemia (CLL) with 17p deletion or mutations of the TP53 gene has a very poor outcome. Optimal treatment of these patients remains a major clinical challenge, and disagreement on the optimal treatment approach exists. Conventional chemo-immunotherapy with rituximab in combination with purine analogues yields lower response-rates and less satisfactory results than for CLL patients with intact p53. Allogeneic stem cell transplantation may allow long-term remissions in this challenging group of patients. In this review, we will discuss current treatment options as well as experimental approaches in clinical trials for CLL patients with deleted or mutated TP53. Particular emphasis will be placed on novel agents with the potential to change clinical practice and future perspectives for the management of these "highest risk" patients.
Subject(s)
Chromosomes, Human, Pair 17/genetics , Genes, p53 , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Sequence Deletion , Tumor Suppressor Protein p53/genetics , Antineoplastic Agents/therapeutic use , Humans , Protein Kinase Inhibitors/therapeutic use , Stem Cell TransplantationABSTRACT
Recent evidence suggests that - in addition to 17p deletion - TP53 mutation is an independent prognostic factor in chronic lymphocytic leukemia (CLL). Data from retrospective analyses and prospective clinical trials show that â¼5% of untreated CLL patients with treatment indication have a TP53 mutation in the absence of 17p deletion. These patients have a poor response and reduced progression-free survival and overall survival with standard treatment approaches. These data suggest that TP53 mutation testing warrants integration into current diagnostic work up of patients with CLL. There are a number of assays to detect TP53 mutations, which have respective advantages and shortcomings. Direct Sanger sequencing of exons 4-9 can be recommended as a suitable test to identify TP53 mutations for centers with limited experience with alternative screening methods. Recommendations are provided on standard operating procedures, quality control, reporting and interpretation. Patients with treatment indications should be investigated for TP53 mutations in addition to the work-up recommended by the International workshop on CLL guidelines. Patients with TP53 mutation may be considered for allogeneic stem cell transplantation in first remission. Alemtuzumab-based regimens can yield a substantial proportion of complete responses, although of short duration. Ideally, patients should be treated within clinical trials exploring new therapeutic agents.