Telomere Length Has Prognostic Impact in B-Cell Chronic Lymphocytic Leukemia (B-CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4768-4768
Author(s):  
Irene Ricca ◽  
Daniela Drandi ◽  
Alberto Rocci ◽  
Mara Compagno ◽  
Roberto Francese ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Telomere Length ◽  
Germ Line ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Staging System ◽  
Good Prognosis ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutational Status

Abstract BACKGROUND. Germinal Center (GC) experience is a basic prognostic feature in B-CLL. Patients with VH-mutated GC-experienced CLL have a good prognosis while those with VH-unmutated GC-inexperienced CLL have a poor prognosis. In a recent study we demonstrated that telomere length (TL) of lymphoproliferative disorders strongly correlates with GC, pre-GC or post-GC origin (Ladetto M et al, Blood 2004). Aims of this study were to further define the relationship between TL and VH mutational status in B-CLL and correlate both these parameters with clinical outcome. PATIENTS AND METHODS. 109 B-CLL patients have been analyzed for telomere restriction fragments (TRF) length and are under evaluation for VH mutational status. All samples were taken at diagnosis or during the "watch and wait" phase. Male were 68, females 41. Median age was 62 years (range 34–87). Fifty-three patients were in stage A, 30 patients were in stage B and 16 were stage C according to Binet staging system. Our patient population has been monitored for a median time of 53 months (range 1–290). Sixty-three patients have been already treated for their disease while 46 have not required treatment, so far. TRF length was evaluated by Southern blot and VH mutational status by direct sequencing, as previously described (Ladetto M et al, Blood 2004). The standard cut-off of 2% deviation from any germ line VH sequence was employed to define VH mutational status. Survival analyses were performed using the Kaplan-Meier method. RESULTS. Overall, median TRF length was 5898bp (range 1737–14837bp). There was no correlation between TRF length and patient age, sex or stage. A cut-off of 4500bp discriminated two subgroups of patients characterized by different clinical outcome in terms of time to first treatment (TTFT) and time to disease progression (TTP) following first line treatment. Patients with TL < 4500bp had a median TTFT of 16 months and a median TTP of 14 months while patients with TL > 4500bp had a median TTFT of 36 months and a median TTP of 50 months (p<0.05 and p<0.005, respectively). VH sequencing is currently available in 72 patients. A comparison between TRF length (using the previously defined 4500bp cut-off) and VH mutational status showed the following: a) 100% concordance between VH-mutated status and TRF length >4500bp; b) 62% concordance between unmutated VH-status and TRF length <4500bp; c) the 10 discordant patients with VH-unmutated status and TRF >4500bp had a clinical outcome similar to that observed in patients with VH-mutated status (median TTFT: 22 months; median TTP:80 months). CONCLUSIONS Our data demonstrate that: 1) TL in B-CLL has a good correlation with VH mutational status; 2) TRF length has prognostic significance in B-CLL in terms of TTFT and TTP; 3) when discordance exists between these two parameters, the clinical behavior seems to be better predicted by TRF length compared to VH mutational status.

KIT Mutations Are Rare Among Elderly AML Patients: A SWOG Report

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2510-2510
Author(s):  
Fabiana Ostronoff ◽  
Megan Othus ◽  
Phoenix A. Ho ◽  
Stephen H. Petersdorf ◽  
Jeanne E. Anderson ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Elderly Patients ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Age Groups ◽  
Prognostic Impact ◽  
Kit Mutation ◽  
Elderly Aml ◽  
Normal Cytogenetics

Abstract Abstract 2510 Background: KIT receptor tyrosine kinase mutations are recurrent genetic alteration found in acute myeloid leukemia (AML) with higher prevalence in those with core binding factor (CBF) AML. Different prognostic significance of these mutations has been found in pediatric and adult AML studies. However, prevalence and prognostic impact of KIT mutations in elderly patients with AML has not been established. In this study, we evaluated the prevalence of KIT mutation and its correlation with cytogenetic, molecular subtypes and clinical outcome in elderly AML patients. Methods: Diagnostic specimens from for 207 patients with AML registered on SWOG trials S-9031 and S-9333 were available for KIT mutation analysis. Both of these clinical protocols enrolled AML patients > 55 years. The samples were analyzed for the presence of KIT mutations via direct sequencing of exons 8 and 17. Results: In the cohort of 207 patients tested, the median age, WBC, and blast count at diagnosis were 68 years (range, 56–88 years), 29,6 × 109/L (range, 7–289 × 109/L) and 67% (0–99%), respectively. Favorable, intermediate and unfavorable cytogenetics were present in 8%, 57% and 26% of the patients, respectively. Nine percent of the patients had cytogenetics abnormalities of unknown significance. Normal cytogenetics was present in 48% of the patients. Fifty-three patients (26%) harbored mutations for FLT3-ITD, 37 (19%) for DNMT3A, 52 (31%) for NPM1 and 50 (24%) for IDH1/2. Only 3 patients were positive for CEBPA mutation. Of the 207 patient specimens tested, KIT exon 17 mutations were detected in 4 patients (2%). Exon 8 mutations were not identified. The characteristics of the 4 patients with KIT mutations are described in the table. Of the 4 patients who harbored the KIT mutation, 2 had intermediate, 1 had unfavorable risk cytogenetics and 1 patient did not have available cytogenetic data. None of the patients with CBF had KIT mutations. In terms of other molecular markers, all 4 patients were wild-type for NPM1, CEBPA, DNMT3A, IDH1/2 and FLT3-ITD. The very small number of KIT mutations in this group of patient precluded correlation between KIT mutations and clinical outcome. Conclusion: The prognostic impact of KIT mutations has been shown to vary according to cytogenetics subgroups. Most studies report a negative prognostic impact of these mutations in patients with CBF AML. The prognostic implications of KIT mutations also seem to vary among different age groups, with pediatric studies indicating they have no prognostic significance and adult studies indicating a negative prognostic impact. To date, there is no large study reporting on the incidence and prognostic impact of KIT mutations in elderly patients with AML. The very low incidence of KIT mutations in our study highlights the age-specific characteristics of AML and may correlate with lower prevalence of CBF translocations in older AML. Further studies investigating the relationship among different somatic mutations in elderly AML patients may help to clarify the pathogenetic mechanism of certain AML subtypes in this patient population. Disclosures: No relevant conflicts of interest to declare.

Shorter Telomeres Are Associated with the Unfavourable Chromosomal Aberrations Del 17p and Del 11q in Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3131-3131
Author(s):  
Ludger Sellmann ◽  
Dirk de Beer ◽  
Marius Bartels ◽  
Holger Nueckel ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Telomere Length ◽  
Chromosomal Aberrations ◽  
Germ Line ◽  
Average Length ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Snp Chip ◽  
Mutational Status

Abstract BACKGROUND: In chronic lymphocytic leukemia (CLL) short telomeres were shown to be associated with mutational status, progression free survival (PFS) and overall survival (Damle et al., 2004). Chromosomal instability increases with shortening of telomeres. Recently, a relationship between telomere length and number of chromosomal aberrations has been shown if telomere length was investigated by quantitative real-time polymerase chain reaction (Tel-PCR) (Roos et al., 2008). The aim of the present study was to correlate average telomere length of individual cells measured by multicolor flow-FISH to established prognostic factors and genomic aberrations. PATIENTS and METHODS: Blood samples from 64 patients with CLL were analyzed. Flow cytometry was performed for quantification of ZAP-70 and CD 38 expression with a cut off at 20%. Immunoglobulin variable heavy chain (IGVH) genes were sequenced. An IGVH gene sequence with less than 98% homology with the corresponding germ-line sequence was considered to be mutated. Chromosomal alterations were investigated by fluorescence in situ hybridization (FISH) with the following gene probes: LSI 13q14, LSI 13q34, CEP 12, LSI 17p13, LSI 11q22–23. Copy number changes were also detected in 18 samples by SNP-chip analysis. The average length of telomere repeats at chromosome ends was measured by multicolor flow-FISH. Values of telomere length from CLL cells were correlated to values of telomere lengths of B lymphocytes from healthy age matched individuals (delta telomere length=Δtel). RESULTS: The average telomere length of the clonal B-cells was short. Patient samples from advanced Binet stages (B/C) had significantly shorter telomeres (Δtel −4.8 ± 1.0 kb) than patients samples from Binet A (Δtel −3.4 ± 1.2 kb, p=0.03). The average telomere length was significantly shorter for ZAP-70+ (Δtel −5.0 ± 0.5 kb) and CD38+ (Δtel −4.9 ± 0.7 kb) patient samples than for ZAP-70− (Δtel −2.4 ± 0.8 kb) and CD38− (Δtel −3.0 ± 1.0 kb) patient samples, respectively (p<0.005, p<0.005). IGVH unmutated CLL samples exhibited significant shorter telomere lengths (Δtel −4.8 ± 0.4 kb) than mutated samples (Δtel −2.8 ± 0.9 kb, p<0.005). Interestingly CLL samples harbouring del 17p and del 11q had significantly shorter average telomere length (Δtel −5.3 ± 0.2 kb, n= 8) than samples without these aberrations (Δtel −4.0 ± 1.2 kb; n= 56, p<0.005). Furthermore we found a tendency of an increase in the number of chromosomal aberrations detected by SNP-chip with shorter telomeres. DISCUSSION: We are able to confirm significant shorter telomeres in CLL samples with unfavourable prognostic factors like advanced Binet stage, positivity for ZAP-70 or CD38 and unmutated IGVH genes compared to their favourable counterparts. CLL samples with the chromosomal aberrations del 17p and del 11q are associated with bad clinical outcome. CLL with these aberrations of the present study demonstrated significantly shorter telomeres compared to cases without these abnormalities. Additional studies relating impact of telomere length on genomic instability detected by SNP-chip are ongoing.

Genomic Aberrations Dramatically Improve The Strong Prognostic Impact Of IGHV Mutational Status In Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1370-1370
Author(s):  
Giovanni Del Poeta ◽  
Dario Ragusa ◽  
Francesco Buccisano ◽  
Michele Dal Bo ◽  
Luca Maurillo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Sanger Sequencing ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Univariate Analysis ◽  
Intermediate Stage ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Mutational Status ◽  
Genomic Aberrations

Abstract CLL is a heterogeneous disease with patients (pts) experiencing rapid disease progression and others living for years without requiring treatment. Recently, next generation sequencing has revealed new molecular alterations, targeting the NOTCH1 and BIRC3 genes which occur in about 10% CLL at diagnosis and correlate with poor outcome. Given the possibility of targeting NOTCH1 and BIRC3 with drugs currently under development, the primary endpoints of our research were: 1) to determine overall survival (OS) upon IGHV, NOTCH1, TP53 and BIRC3 in univariate analysis; 2) to correlate these genomic aberrations with other biological or clinical prognostic factors, and finally 3) to confirm NOTCH1, BIRC3 and TP53 as independent prognostic factors. We investigated 475 pts with a median age of 65 years (range 33-89), whose 160 had low Rai stage, 301 intermediate stage and 14 high stage. NOTCH1 mutations (mut) were studied by ARMS PCR for c.7544-7545delCT and by Sanger sequencing of NOTCH1 exon 34. Mutations of TP53 were analysed by DNA direct sequencing, while BIRC3 disruption (disr) was studied by Sanger sequencing for mutations and by interphase FISH for deletions. All these alterations were studied at diagnosis or before any chemotherapeutic approach. NOTCH1mut and TP53mut pts were 52 (10.9%) and 36/475 (7.6%), respectively. Thirty four patients were BIRC3mut (7.2%) and 26 BIRC3 deleted (5.5%) for a total of 46 cases (9.7%) BIRC3disr. NOTCH1, TP53 and BIRC3 alterations were mutually exclusive. There were significant correlations between NOTCH1 (P<0.00001), TP53 (P=0.004), BIRC3 status (P=0.00004) and IGHV mutations. Concerning FISH cytogenetics (460 patients), a significant correlation (P<0.0001) was found between NOTCH1mut and trisomy 12 (20/62; 32%). TP53mut were strictly associated with del17p (15/25; 60%; P<0.0001), while BIRC3disr was found mainly within 11q22-q23 deletions subset (22/46;49%; P<0.0001). With regard to clinical outcome, 30 (83%) of 36 TP53mut pts (P=0.00009), 47 (90%) of 52 NOTCH1mut (P<0.00001) and 40 (87%) of 46 BIRC3disr pts had received chemotherapy at the time of analysis. Twenty nine NOTCH1mut (56%), 15 TP53mut (42%) and 18 BIRC3disr (39%) pts underwent at least two lines of treatment (P<0.0001). Noteworthy, shorter OS was observed in IGHV unmutated (UM) patients (12% vs 80% at 18 years, P<0.00001), in NOTCH1mut pts (12% vs 71% at 16 years, P<0.00001), in TP53mut pts (9% vs 76% at 14 years, P<0.00001) and in BIRC3disr pts (29% vs 65% at 16 years, P=0.00001). To further explore the prognostic impact of NOTCH1mut, TP53mut and BIRC3disr, we investigated them within the UM (153 pts) IGHV subset, notoriously at worst prognosis. As a matter of fact, NOTCH1mut (16% vs 45% at 14 years, P=0.012), TP53mut (0% vs 43% at 13 years, P=0.002) and BIRC3disr (0% vs 57% at 11 years, P=0.011) pts showed significant shorter OS [Figure]. Within the mutated IGHV subgroup we obtained similar results. In multivariate analysis of OS, TP53mut (HR 5.2, P<0.00001), age >60 years (HR 3.8, P=0.00002), IGHV UM status (HR 0.30, P=0.0001), intermediate/high Rai stages (HR 2.8, P=0.0002), NOTCH1mut (HR 2.6, P=0.001), and BIRC3disr (HR 2.5, P=0.005) were confirmed to be independent adverse prognostic factors. Noteworthy, here, we demonstrated that genomic aberrations are able to improve the historical prognostic ability of the IgHV mutational status. In conclusion, genomic aberrations, particularly TP53mut, NOTCH1mut and BIRC3disr should be considered as novel important prognostic parameters in CLL and therefore they have to be necessarily considered in updated scoring prognostic systems. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Relation of Gene Expression Phenotype to Immunoglobulin Mutation Genotype in B Cell Chronic Lymphocytic Leukemia

2001 ◽  
Vol 194 (11) ◽  
pp. 1639-1648 ◽  
Author(s):  
Andreas Rosenwald ◽  
Ash A. Alizadeh ◽  
George Widhopf ◽  
Richard Simon ◽  
R. Eric Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Germ Line ◽  
Gene Expression Signature ◽  
Lymphocytic Leukemia ◽  
Common Mechanism ◽  
Human Leukemia ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

The most common human leukemia is B cell chronic lymphocytic leukemia (CLL), a malignancy of mature B cells with a characteristic clinical presentation but a variable clinical course. The rearranged immunoglobulin (Ig) genes of CLL cells may be either germ-line in sequence or somatically mutated. Lack of Ig mutations defined a distinctly worse prognostic group of CLL patients raising the possibility that CLL comprises two distinct diseases. Using genomic-scale gene expression profiling, we show that CLL is characterized by a common gene expression “signature,” irrespective of Ig mutational status, suggesting that CLL cases share a common mechanism of transformation and/or cell of origin. Nonetheless, the expression of hundreds of other genes correlated with the Ig mutational status, including many genes that are modulated in expression during mitogenic B cell receptor signaling. These genes were used to build a CLL subtype predictor that may help in the clinical classification of patients with this disease.

The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2850-2858 ◽  
Author(s):  
Peter Dreger ◽  
Stephan Stilgenbauer ◽  
Axel Benner ◽  
Matthias Ritgen ◽  
Alexander Kröber ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Lymphocytic Leukemia ◽  
Study Entry ◽  
Prognostic Impact ◽  
Cox Regression Analysis ◽  
Mutational Status

Abstract To assess the therapeutic value of sequential high-dose therapy (SHDT) including autologous stem cell transplantation in chronic lymphocytic leukemia (CLL) we performed a risk-matched comparison between 66 patients who had undergone a uniform SHDT regimen and a database of 291 patients treated conventionally. Matching variables were age, Binet stage, IgVH (variable region of the immunoglobulin heavy chain) gene mutational status, and lymphocyte count. Forty-four pairs fully matched for all 4 variables were identified. Patient groups were well balanced for additional risk factors including adverse genomic abnormalities and CD38 expression. With an overall median follow-up time of 70 and 86 months, respectively, survival was significantly longer for the SHDT patients than for the conventionally treated patients when calculated from diagnosis (hazard ratio [HR] 0.39; P = .03 [log rank]) or from study entry (HR 0.32; P = .006). The benefit for the SHDT group remained significant when the analyses were restricted to those 58 patients who had an unmutated VH status. Cox regression analysis confirmed SHDT as independent favorable prognostic factor for survival from diagnosis (HR 0.38, P = .04) as well as from study entry (HR 0.38, P = .03). These data suggest a survival benefit for patients with poor-risk CLL receiving SHDT during the course of their disease. (Blood. 2004;103:2850-2858)

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

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3322-3329 ◽  
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.

scholarly journals Chronic Lymphocytic Leukemia in Kuwait

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5467-5467
Author(s):  
Salem Alshemmari ◽  
Ramesh Pandita ◽  
Abdulaziz Hamadah ◽  
Ahmad Alhuraiji
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Mutational Analysis ◽  
Staging System ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Western Countries ◽  
Mutational Status ◽  
Study Results ◽  
History Of

Background :Chronic lymphocytic leukemia (CLL) is common malignancy in Western countries. However, little known about this disease entity in our area. This study exploring the biology in out patients' population. Method:Patients with confirmed CLL under IGHV and TP53 mutational analysis at presentation or during follow up. We also integrated other clinical and biological parameter in this study. Results: A total of 137 cases were analyzed, median age 61 years (range:34-89); 30% of the cases age was<55 years at presentation. There was 108 males vs. 29 females M:F ratio 3.7. Two patients gave a family history of CLL, while 1 patient gave a history of other lymphoproliferative disorders. Binet staging system available in 134 cases, A: 109 (81.3%), B: 12 (9%), C:13 (9.7%). B2 macroglobulin elevated in 40/112 (36%) cases and 10/103 (10%) had M-spike. CD38 positivity reported in 37/112 (33%) of cases. Cytogenetics data evaluable in 85 cases: isolated del(13q): 35%, isolated trisomy 12 (16.5%), del(11q) (4.5%), del(17p)(2.4%). IGHV mutational status mutated vs unmutated: 40% vs 60%. Cases with available treatment information on 132 cases. Fifty cases required treatment due to disease progression. First line treatment Bendamustine-Rituximab (BR) 3 cases, Fludarabine Cyclophosphamide Rituximab (FCR) 30 cases and Chlorambucil with anti-CD 20 antibody 6 cases. At the time of review, 3 cases on ibrutinib (2 in 3rdline and 1 case in the 4thline). Conclusion: This is the first study to shed light on CLL in our area. There are biological differences between our patients' population and the western countries. Disclosures Pandita: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 2049-2053 ◽  
Author(s):  
Matthias Ritgen ◽  
Alexandra Lange ◽  
Stephan Stilgenbauer ◽  
Hartmut Döhner ◽  
Christian Bretscher ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Germ Line ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Heavy Chain Gene ◽  
Adverse Prognostic Factor ◽  
Mutational Status ◽  
Variable Heavy ◽  
Vh Genes ◽  
Gene Status

An unmutated germ line configuration of the immunoglobulin variable heavy-chain gene (VH) has emerged to be a crucial adverse prognostic factor in chronic lymphocytic leukemia (CLL) under conventional treatment. The purpose of the present study was to investigate whether the VH mutational status retains its prognostic value in CLL also in the setting of autologous stem cell transplantation (SCT). Therefore, we investigated the mutational status in 58 patients with CLL who underwent myeloablative radiochemotherapy with SCT. Rearranged VH genes were analyzed by multiplex polymerase chain reaction (PCR) and direct sequencing using FR1 family–specific primers and JH consensus primers. Twenty patients (34%) showed less than 98% homology compared with germ line VH sequences and were considered as mutated, whereas 38 patients (66%) had an unmutated VH status (median mutational rate of 0%; range, 0%-1.7%). An unmutated VHconfiguration was strongly correlated with the presence of short lymphocyte doubling time (P = .003) and high lymphocyte count (P = .005). Time to clinical relapse and time to recurrence of monoclonal B cells as assessed by consensus IgH CDR3 PCR was significantly shorter in the group with unmutated VH genes (2-year probability 19% versus 0%,P = .0008, and 34% versus 9%, P = .0006, respectively). These results show that in CLL, an unmutated VH gene status of the tumor clone remains an adverse prognostic factor after SCT. Nevertheless, the hitherto only 3 deaths and the median treatment-free interval of 49 months in the unmutated cohort suggest a beneficial effect of SCT for this high-risk population in comparison to conventional treatment.

Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study

2006 ◽  
Vol 24 (24) ◽  
pp. 3904-3911 ◽  
Author(s):  
Peter Paschka ◽  
Guido Marcucci ◽  
Amy S. Ruppert ◽  
Krzysztof Mrózek ◽  
Hankui Chen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Core Binding Factor ◽  
Relapse Risk ◽  
Binding Factor ◽  
Acute Myeloid

Purpose To analyze the prognostic impact of mutated KIT (mutKIT) in core-binding factor acute myeloid leukemia (AML) with inv(16)(p13q22) and t(8;21)(q22;q22). Patients and Methods Sixty-one adults with inv(16) and 49 adults with t(8;21), assigned to postremission therapy with repetitive cycles of higher dose cytarabine were analyzed for mutKIT in exon 17 (mutKIT17) and 8 (mutKIT8) by denaturing high-performance liquid chromatography and direct sequencing at diagnosis. The median follow-up was 5.3 years. Results Among patients with inv(16), 29.5% had mutKIT (16% with mutKIT17 and 13% with sole mutKIT8). Among patients with t(8;21), 22% had mutKIT (18% with mutKIT17 and 4% with sole mutKIT8). Complete remission rates of patients with mutKIT and wild-type KIT (wtKIT) were similar in both cytogenetic groups. In inv(16), the cumulative incidence of relapse (CIR) was higher for patients with mutKIT (P = .05; 5-year CIR, 56% v 29%) and those with mutKIT17 (P = .002; 5-year CIR, 80% v 29%) compared with wtKIT patients. Once data were adjusted for sex, mutKIT predicted worse overall survival (OS). In t(8;21), mutKIT predicted higher CIR (P = .017; 5-year CIR, 70% v 36%), but did not influence OS. Conclusion We report for the first time that mutKIT, and particularly mutKIT17, confer higher relapse risk, and both mutKIT17 and mutKIT8 appear to adversely affect OS in AML with inv(16). We also confirm the adverse impact of mutKIT on relapse risk in t(8;21) AML. We suggest that patients with core-binding factor AML should be screened for mutKIT at diagnosis for both prognostic and therapeutic purposes, given that activated KIT potentially can be targeted with novel tyrosine kinase inhibitors.

Notch1 Mutations in Adult T Lymphoblastic Lymphoma and T-ALL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2286-2286
Author(s):  
Frederic Baleydier ◽  
Arnauld Simon ◽  
Julie Bergeron ◽  
Corinne Millien ◽  
Kheira Beldjord ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Pediatric Patients ◽  
Direct Sequencing ◽  
Good Prognosis ◽  
Lymphoblastic Lymphoma ◽  
Prognostic Impact ◽  
Maturation Arrest ◽  
Favorable Prognosis ◽  
T Lymphoblastic Lymphoma ◽  
Notch1 Mutations

Abstract Notch1 is recognised to be involved in human T-ALL oncogenesis, initially by implication of its intracellular domain in the rare translocation t(7;9) and more recently with the description of mutations in NOTCH1 exons coding the heterodimerisation (HD) +/− PEST domains in 50% of T-ALL. Favorable prognosis impact of Notch1 mutations has been shown in pediatric patients. Little data is available regarding Notch mutations in adult T-ALL, and even less in adult T Lymphoblastic lymphoma (T-LBL). We have therefore searched for Notch1 mutations in adult T-ALL and T-LBL, all of which have undergone comparable, TCR and oncogene based classification (TLX1/3, SIL-TAL1, CALM-AF10, LMO1/2, TAL1 and LYL1). We searched for mutations in exons 26, 27 and 34 by direct sequencing in 46 T-ALL (median age 27,5y. range 16–54; 6 < 18y) and 32 T-LL (median 31y., range 16–70y.; 3 < 18y.). Notch1 mutations were identified in 22/46 (48%) of T-ALL and 16/32 (50%) of T-LBL. The type of mutations differed, insofar as HD only mutations were seen in 16/22 (73%) of mutated T-ALL but only 4/16 (25%) of mutated T-LL whereas PEST only mutations were seen in 2/22 (9%) T-ALL compared to 8/16 (50%) of T-LBL. The incidence of HD and PEST mutations was identical in T-ALL (4/16; 25%) and T-LBL (6/22; 27%). Combining T-ALL and T-LBL, TLX1hi or TLX3 expression was seen in 7/71 (10%) and 5/71 (7%) cases respectively. Notch1 mutations were seen in 7/7 TLX1+ cases but only 1/5 TLX3 (p=0.004). With respect to stage of maturation arrest, Notch mutations in T-ALL were relatively rare in mature TCR+ cases (2/15 vs. 20/31 p=0.001), whereas they were found at all stages of maturation arrest in T-LBL. These data demonstrate that Notch 1 mutations are as frequent in T-LBL as T-ALL, but more frequently involve the PEST domain. They are in favour of preferential occurrence of NOTCH1 mutations in TLX1 relative to TLX3 proliferations, suggesting that evaluation of prognostic impact of Notch1 should not be performed independently of evaluation of TLX1/3 status, since TLX1 generally identifies good prognosis and TLX3 poor prognosis T-ALL. Within the 46 LALA94 adult T-ALLs, Notch1 mutated cases were of marginally superior prognosis (p=0.50); this is currently being evaluated within the ongoing adult GRAALL03 T-ALL trial.

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