TP53 Mutations in Low-Risk Myelodysplastic Syndromes With del(5q) Predict Disease Progression

2011 ◽  
Vol 29 (15) ◽  
pp. 1971-1979 ◽  
Author(s):  
Martin Jädersten ◽  
Leonie Saft ◽  
Alexander Smith ◽  
Austin Kulasekararaj ◽  
Sabine Pomplun ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Clinical Decision Making ◽  
P53 Protein ◽  
Low Risk ◽  
Disease Stage ◽  
International Prognostic Scoring System ◽  
P53 Overexpression ◽  
Tp53 Mutations ◽  
Increased Risk

Purpose To determine the frequency of TP53 mutations and the level of p53 protein expression by immunohistochemistry (IHC) in low-risk myelodysplastic syndromes (MDS) with del(5q) and to assess their impact on disease progression. Patients and Methods Pre- and postprogression bone marrow (BM) samples from 55 consecutive patients with International Prognostic Scoring System low risk (n = 32) or intermediate-1 risk (n = 23) were studied by next-generation sequencing of TP53. IHC for p53 was performed on 148 sequential BM samples. Results TP53 mutations with a median clone size of 11% (range, 1% to 54%) were detected in 10 patients (18%) already at an early phase of the disease. Mutations were equally common in low-risk and intermediate-1–risk patients and were associated with evolution to acute myeloid leukemia (5 of 10 v 7 of 45; P = .045). Nine of 10 patients carrying mutations showed more than 2% BM progenitors with strong p53 staining. The probability of a complete cytogenetic response to lenalidomide was lower in mutated patients (0 of 7 v 12 of 24; P = .024). Conclusion By using sensitive deep-sequencing technology, we demonstrated that TP53 mutated populations may occur at an early disease stage in almost a fifth of low-risk MDS patients with del(5q). Importantly, mutations were present years before disease progression and were associated with an increased risk of leukemic evolution. TP53 mutations could not be predicted by common clinical features but were associated with p53 overexpression. Our findings indicate a previously unrecognized heterogeneity of the disease which may significantly affect clinical decision making.

Do Unexpected and Cryptic FISH Lesions Of Chromosomally Normal MDS Patients Have Any Prognostic Relevance?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1549-1549
Author(s):  
Paolo Bernasconi ◽  
Irene Dambruoso ◽  
Marina Boni ◽  
Paola Maria Cavigliano ◽  
Ilaria Giardini ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Low Risk ◽  
Disease Stage ◽  
Intermediate Risk ◽  
Disease Evolution ◽  
Prognostic Relevance ◽  
Increased Risk ◽  
Very High ◽  
Disease Specific

Abstract Conventional cytogenetic (CC) still remains a mandatory step in the routine diagnostic work-up of every MDS patient (pt), is one of the major determinant of disease outcome and guides potential treatment decisions. However, CC is not informative in about 50% of chromosomally normal (CN) pts and provides limited information in those with very rare defects even if the revised IPSS cytogenetic categories have tried to overcome this drawback. More sensitive techniques (aCGH, SNP-a and NGS), still used in the research setting only, suggest that CN pts may instead contain novel unexpected chromosomal lesions which prognosis is still undefined. Thus, the principal goal of our study was to establish whether FISH with disease specific probes (i.e. for chromosomal regions most commonly affected in MDS) along with non-disease specific probes (i.e. for regions which alteration in MDS has been demonstrated by aCGH only) may effectively unmask clonal cryptic defects. Other aims were to establish the nature of these defects, to identify the potentially targeted genes and to estimate their possible prognostic relevance. The one-hundred twenty-seven consecutive CN MDS pts of the present study came to our observation in the period January 2003-December 2012. They were forty-nine females and seventy-eight males, median age 66 years (range 24-88). Twenty-one pts were diagnosed as RARS, 29 as RA, one as CRMDS, one as U-MDS, 25 as RCMD, 26 as RAEB-1 and 24 as RAEB-2. On CC 122 pts presented a normal karyotype and five no mitotic figures. Considering the revised IPSS score, 62 pts were considered very low-risk, 32 low-risk, 23 intermediate risk, 8 high-risk and 2 very high-risk. Median follow-up was 22 months (range 1-90). At the time of the study nine pts have died. FISH probes were chosen based on the frequency of their involvement in MDS and their Mb position determined using UCSC genome browser on Human Mar. 2003 assembly. They were obtained from BACPAC Resources Center at C.H.O.R.I. (Oakland, USA), labelled and applied as previously described. These probes were: RP11-912D8 (19q13.2); RP11-196P12 (17q11.2); RP11-269C4 (14q12); RP11-351O1 (10q21.3); RP11-144G6 (10q11.2); RP11-122A11 (7q34); RP11-951K18 (5q13.1); RP11-101K5 (4p14); RP11-544H14 (2q33). i-FISH cut-off values were fixed at 10%. Thirty-one pts (24.4%) presented at least a single defect, always represented by deletions or gains of chromosomal material. Among them 8 pts (25.8%) presented at least two defects. Bands most commonly targeted by deletions/amplifications were 19q13.2 (61.3%), 14q12 (32.2%), 17q11.2 (16.1%), 5q13.1 (12.9%), 7q34 (12.9%), 4p14 (9.6%). Deletions of bands 10q11.2, 10q21.3 and 2p33 were more rare. As the RMD-1 gene, involved in DNA double strand breaks and homologous recombination, maps at band 19q13.2, the most commonly deleted chromosomal area, additional molecular tests are being developed to analyse this gene. An abnormal FISH pattern was observed in 2/21 (9.5%) RARS, in 7/29 (24.1%) RA, in 5/25 (20.0%) RCMD, in 8/26 (30.6%) RAEB-1 and in 9/24 (37.5%) RAEB-2. Considering IPSS, an abnormal FISH pattern was revealed in 7/62 (11.3%) very low-risk, in 8/32 (25%) low-risk, in 10/23 (43.4%) intermediate risk, in 5/8 (62.5%) high-risk and in 1/2 very high-risk patients. Disease evolution occurred in a total of 34 pts (3 RARS, 7 RA, 5 CRMD, 11 RAEB-1 and 8 RAEB-2), 16 (one RARS, 3 RA, 2 CRMD, 6 RAEB-1 and 4 RAEB-2) with an abnormal FISH pattern. All the 8 patients with at least two chromosomal deletions experienced disease progression. In conclusion, i) FISH reveals novel unexpected karyotype defects, most commonly deletions pinpointing genes involved in DNA repair, in about 24.4% of CN MDS; ii) band 19q13.2 deletion is the most common defect, frequently associated with disease evolution; ii) an abnormal FISH pattern is correlated with an advanced disease stage and an intermediate/high revised IPSS score; iii) >two lesions are associated with an increased risk of disease progression. Disclosures: No relevant conflicts of interest to declare.

P53 Protein Expression Correlates with Adverse Outcome in Low-Risk Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5505-5505
Author(s):  
Francesca Donatelli ◽  
Austin G. Kulasekararaj ◽  
Alexander e Smith ◽  
Jon Salisbury ◽  
Syed A Mian ◽  
...  
Keyword(s):  
Protein Expression ◽  
Tp53 Mutation ◽  
P53 Protein ◽  
Progression Free Survival ◽  
Low Risk ◽  
P53 Overexpression ◽  
P53 Expression ◽  
Free Survival ◽  
Tp53 Mutations ◽  
P53 Protein Expression

Abstract Background The presence of diverse spectrum of mutations in myelodysplastic syndromes (MDS) has largely revolutionized the understanding of the disease. Although certain mutations have doubtful prognostic significance, the adverse impact of TP53 mutation is irrefutable in all publications. We and others have shown the strong correlation between presence of TP53 mutation and overexpression of p53 by immunohistochemistry (IHC). This evidence provides the rationale for the evaluation of p53 overexpression which is available in routine diagnostic workup, as a surrogate marker to predict TP53 mutations. Additionally, we predicted that the overexpression of p53 might be an independent prognosticator, even in the absence of TP53 mutations or RPS14 haploinsufficiency, in low risk MDS. In our study,we analyzed the p53 protein expression in a cohort of 277 'lower risk' MDS patients and compared the clinico-pathological features, overall survival and risk of progression and evolution to AML with respect to p53 IHC status. Methods This study enrolled 277 adult low risk MDS patients seen at King's College Hospital between March 2009 and February 2016. All marrow samples were assessed for p53 expression (intensity and proportion of cells) and scored using a Modified Quick Score (MQS). MQS ≥2 was chosen to define p53-positive staining. The median follow-up was 18.7 months [95% confidence interval (CI), 16.5-21.0 months]. Results According to WHO categories, the predominant group was RCMD (78%). Patients were either IPSS low (n=134, 48%) or int-1 (n=91, 33%). We included 52 (19%) pts for whom the IPSS category was not available, due to the lack or failed cytogenetic data, but these were low-risk WHO categories with no excess of blasts. IPSS-R categories were very low 103 (37%), low 77 (28%), intermediate 38 (14%) and high risk 7 (3%). Overall, 19 (7%) patients progressed to AML and 41 (15%) patients died of which 25 (61%) were disease-related deaths. Of the 277 patients, 148 (53%) showed p53 protein expression with MQS ≥ 2 and were considered "p53-positive" patients (p53+). The p53 stain intensity was negative in 125 (45%), weak in 84 (30%), moderate in 40 (14%) and strong in 28 (11%). Seventy six (28%) patients had >5% p53 staining cells. p53 expression correlated with a higher age at diagnosis (median age 64 vs. 60 years, p=0.01). lower haemoglobin levels (9.8 vs 11 g/dL, p=0.002), but a higher platelets count (139 vs 99 x109/L, p =.003) (Table 1). This significance persisted even on exclusion of patients with 5q- and MDS/MPN. P53+ did not correlate with any cytogenetic risk group or degree of fibrosis. Sequencing data was available in 121 patients with 63 harbouring somatic mutations. Among these patients, only 3 showed the TP53 gene mutation; all of them were classified as positive when assessed for p53 stain (MQS≥2), showing that the nuclear staining reflects underlying TP53 mutations in such cases. Additionally, presence of SF3B1 mutation correlated strongly with p53+ (p=0.02). Patients with p53+ had a significantly shorter OS compared with those with p53- (figure 1a) with 2yr and 4yr survival probability of 87% &68% vs 95% & 90% , respectively (p=0.03 ). Analysis of progression-free survival (progression to AML, cytogenetic evolution, increase of blasts or fibrosis) showed that patients with p53 expression had a significantly shorter PFS compared to patients without p53 expression (Figure 1b): 2yr & 4yr PFS 70% & 54% vs 85% &75% respectively, p=0.01). Multivariate analysis confirmed the independent prognostic value of p53 expression for PFS (p=0.013, HR 2.6, 95% CI 1.2-5.2). Conclusion In conclusion, our study showed that p53 overexpression by IHC, represented as MQS cutoff ≥ 2, correlates with features of poor prognosis, such as more advanced age at diagnosis, lower haemoglobin levels and shorter overall survival, adversely impacting progression-free survival. p53 IHC in MDS patients may represent an important, easily available, cheap and applicable prognostic tool and it should be considered for auxiliary analysis when determining the therapeutic options for a patient. The p53+ predicts poor outcome, especially disease progression, independent of the TP53 mutation status, indicating an alternate yet undefined pathway for p53 overexpression. Figure 1(a) Disease-related OS (a) and PFS (b) in patients with low-risk MDS according to their p53 expression-status Figure 1(a). Disease-related OS (a) and PFS (b) in patients with low-risk MDS according to their p53 expression-status Figure 1(b) Figure 1(b). Disclosures No relevant conflicts of interest to declare.

scholarly journals The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1144
Author(s):  
Chiara Chiereghin ◽  
Erica Travaglino ◽  
Matteo Zampini ◽  
Elena Saba ◽  
Claudia Saitta ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Clinical Relevance ◽  
Driver Mutations ◽  
Significant Information ◽  
Hematopoietic Stem ◽  
Probability Of Survival ◽  
Mutational Status ◽  
Increased Risk ◽  
Risk Of Disease

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

scholarly journals The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy

2019 ◽  
Vol 20 (21) ◽  
pp. 5482 ◽  
Author(s):  
Mitsuhiro Nakamura ◽  
Takeshi Obata ◽  
Takiko Daikoku ◽  
Hiroshi Fujiwara
Keyword(s):  
Cervical Cancer ◽  
Endometrial Cancer ◽  
Malignant Tumors ◽  
P53 Protein ◽  
P53 Gene ◽  
Phase Iii ◽  
Significant Prognostic Factor ◽  
Double Positive ◽  
P53 Overexpression ◽  
Tp53 Mutations

Dysfunction of p53 is observed in the many malignant tumors. In cervical cancer, p53 is inactivated by degradation through the complex with human papilloma virus (HPV) oncoprotein E6 and E6-associated protein (E6AP), an E3 ubiquitin protein ligase. In endometrial cancer, overexpression of p53 in immunohistochemistry is a significant prognostic factor. A discrepancy between p53 overexpression and TP53 mutations is observed in endometrioid endometrial cancer, indicating that the accumulation of p53 protein can be explained by not only gene mutations but also dysregulation of the factors such as ERβ and MDM2. Furthermore, the double-positive expression of immunoreactive estrogen receptor (ER) β and p53 proteins is closely associated with the incidence of metastasis and/or recurrence. High-grade serous ovarian carcinoma (HGSC) arises from secretary cells in the fallopian tube. The secretary cell outgrowth (SCOUT) with TP53 mutations progresses to HGSC via the p53 signature, serous intraepithelial lesion (STIL), and serous intraepithelial carcinoma (STIC), indicating that TP53 mutation is associated with carcinogenesis of HGSC. Clinical application targeting p53 has been approved for some malignant tumors. Gene therapy by the adenovirus-mediated p53 gene transfer system is performed for head and neck cancer. A clinical phase III trial using MDM2/X inhibitors, idasanutlin (RG7388) combined with cytarabine, is being performed involving relapse/refractory acute myeloid leukemia patients. The use of adenoviruses as live vectors which encode wild-type p53 has given promising results in cervical cancer patients.

Low-Density Lipoprotein Subfractionation: What Is the Role of the Lab When Reporting Discrepant Results?

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S8-S9
Author(s):  
Nicholas E Larkey ◽  
Leslie J Donato ◽  
Allan S Jaffe ◽  
Jeffrey W Meeusen
Keyword(s):  
Coronary Artery ◽  
High Risk ◽  
Clinical Decision Making ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Risk ◽  
Lipid Lowering ◽  
Low Density ◽  
Small Dense Ldl ◽  
Increased Risk

Abstract Plasma concentrations of low-density-lipoprotein cholesterol (LDL-C) are directly associated with risk for coronary artery disease (CAD). Multisociety guidelines define LDL-C&gt;160mg/dL as a risk factor for CAD and LDL-C&gt;190mg/dL as an indication for lipid lowering medication, regardless of other clinical factors. Subfractionation of LDL according to size (LDL-s) enables differentiation between two LDL phenotypes: large-buoyant LDL and small-dense LDL. The small-dense LDL phenotype reportedly conveys increased risk for CAD. Major societies do not recommend LDL subfractions be used for clinical decision making and most payers do not cover LDL subfraction testing. Despite these restrictions, LDL subfraction is routinely requested by clinicians. Nuclear magnetic resonance (NMR) spectroscopy measures LDL-C and LDL-s. Following inquiries regarding interpretation of conflicting LDL-C and LDL-s results, we investigated associations between LDL-C and LDL-s measured by NMR in order to determine how often they provide contradicting or additive information. Verification of NMR LDL-C accuracy was confirmed by ß-quantification in a subset of patient samples (n=250). The average bias was -4.5mg/dL and the correlation coefficient was 0.92. High-risk was defined as LDL-C&gt;160mg/dL or LDL-s&lt;20.5 nm (small-dense LDL); and low-risk was defined as LDL-C&lt;70mg/dL or LDL-s&gt;20.5nm (large-buoyant LDL). In 26,710 clinical NMR analyses, the median LDL-C was 94.0mg/dL (range:5-436mg/dL) with median LDL-s of 20.8 nm (range:19.4–23.0nm). LDL-s moderately correlated with LDL-C (Ï#129;=0.51;p&lt;0.01). Small-dense-LDL was identified in only 18% (407/2,191) of patients with elevated LDL-C (&gt;160mg/dL) and was more common (73.2% of 6,093) in patients with low LDL-C (&lt;70mg/dL;p&lt;0.001). Associations with CAD were investigated among patients without cholesterol-lowering medication treatment referred for angiography (n=356). CAD (defined as stenosis &gt;50% in one or more coronary artery) was diagnosed in 14% (1/7) of subjects with low LDL-C (&lt;70mg/dL) compared to 59% (47/80) of subjects with elevated LDL-C (p=0.01). When stratifying by LDL-s, CAD was diagnosed in 50% (57/115) of subjects with small-dense LDL compared to 43% (104/241) of subjects with large-buoyant LDL (p=0.2). Small-dense LDL was identified in only 33% (26/80) of cases with elevated LDL-C. Limiting to subjects with elevated LDL-C, CAD was diagnosed in 50% (13/26) of subjects with concordant (high-risk) small-dense LDL compared to 61% (33/54) of subjects with discordant (low-risk) large-buoyant LDL (LDL-s&gt;20.5nm) (p=0.3). Our data confirm that LDL-s subfraction measured by NMR is reported discordantly in most cases when LDL-C is unequivocally high or low. Furthermore, CAD diagnosis was significantly associated with LDL-C, but not with LDL-s. Our data also show that in discrepant samples, elevated LDL-C correlates better with disease state compared to LDL-s. Therefore, LDL-s should not be used to justify treatment decisions in patients with elevated LDL-C. Laboratories should consider carefully whether or not to report LDL-s when it is known that misleading and discordant values will be reported in a majority of cases.

Short Telomeres Before Lenalidomide Treatment Predict Leukemic Progression In Patients with Myelodysplastic Syndrome and Deletion 5q

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 30-30
Author(s):  
Gudrun Göhring ◽  
Kathrin Lange ◽  
Winfried Hofmann ◽  
Kirsten Vang Nielsen ◽  
Eva Hellström-Lindberg ◽  
...  
Keyword(s):  
Disease Progression ◽  
Telomere Length ◽  
Cytogenetic Response ◽  
Length Measurement ◽  
Study Entry ◽  
Disease Stage ◽  
Fish Analysis ◽  
Leukemic Transformation ◽  
Telomere Shortening ◽  
Increased Risk

Abstract Abstract 30 Lenalidomide has been shown to induce transfusion independence and cytogenetic response in a high proportion of patients with MDS and isolated 5q deletion (del5q). However, some of these patients progress into acute myeloid leukemia, particularly those who do not show an erythroid or cytogenetic response. Yet the mechanisms inducing the leukemic transformation in patients with MDS and del(5q) are mainly unclear. Since dysfunctional telomeres play an important role in the development of genetic instability and shorter telomeres are associated with advanced MDS and AML, we reasoned whether telomere shortening may contribute to leukemic progression in patients with MDS and del5q. This study included 14 patients with transfusion-dependent anemia and low- or intermediate-1-risk MDS enrolled in the studies MDS-003 (n=42) or MDS-004 (n=260) who were treated with lenalidomide according to the study protocols. Written informed consent was provided according to the Declaration of Helsinki. Seven patients progressed into RAEB-1 or AML while on study and 7 patients did not. Time span between initial diagnosis and study entry was similar (median 51.3 and 44.4 months respectively in the patients with and without leukemic progression). Combined fluorescence R-banding and T/C-FISH analysis to determine the telomere length of each individual chromosome was performed as described earlier (K Lange et al, Genes Chromosomes Cancer, 2010). Telomere length at study entry was 6.1 kb (range 4.8 to 7.9 kb) in patients with MDS and del5q who later underwent leukemic transformation. Patients without later disease progression had a median telomere length of 9.3 kb (range 8.4 to 10.2 kb). Thus, patients who progressed after a median of 29 months (range 5 to 51 months) had significantly shorter telomeres than patients who had a cytogenetic response or stable disease (p<0.001). Notably, during treatment with lenalidomide, the group of patients who underwent leukemic transformation had a median increase in telomere length of 2.4 kb (range: 0.5 to 3.4 kb, p<0.02). In contrast, no relevant telomere elongation was observed in patients who did not undergo leukemic progression (9.3 kb at study entry and 8.8 kb after a median of 31 months (range 11 to 52 months) following lenalidomide treatment). Furthermore, telomere length was independent of the presence of additional aberrations. Two patients with additional aberrations and subsequent progression had shorter telomeres than another patient with additional aberrations who did not undergo progression (5.7 kb and 7.9 kb versus 10.2 kb). Two patients with disease progression showed a mosaic of normal and aberrant metaphases in the bone marrow. In both cases, telomeres of the normal metaphases were longer than the telomeres of aberrant metaphases (9.1 kb versus 6.9 kb; 9.7 kb versus 5.5 kb, respectively). Three of the patients who underwent leukemic progression acquired additional chromosome aberrations and developed complex karyotypes. They had a median telomere length of 6.4 kb (range: 4.8 to 7.9 kb), which was not significantly different from the median telomere length of 6.0 kb (range: 4.8 to 7.5 kb) in the group of patients who showed an isolated del5q during the leukemic transformation. Thus, telomere shortening not only preferentially occurred in cells with del(5q), it was also independent of clonal evolution. Although the underlying mechanisms leading to excessive telomere shortening in MDS pathogenesis remain unclear, telomere shortening seems to predispose to leukemic transformation in patients with MDS and del5q. Currently, factors predictive for increased risk of leukemic transformation are lacking and only clinical, morphological and cytogenetic follow-up investigations provide meaningful information regarding treatment success and disease stage. Identification of a prognostic marker to identify patients at increased risk for leukemic progression at an early time point before lenalidomide treatment would greatly improve patient care. Telomere length measurement in these patients may therefore provide a diagnostic tool for predicting treatment response and disease outcome following lenalidomide treatment. Clearly, these data need confirmation in larger patient cohorts, before telomere length measurement can be used for risk assessment prior to starting lenalidomide treatment. Disclosures: Göhring: Celgene Corp.: Consultancy. Giagounidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Significant Correlation Between the Degree of WT1 Expression and the International Prognostic Scoring System Score in Patients With Myelodysplastic Syndromes

2003 ◽  
Vol 21 (10) ◽  
pp. 1988-1995 ◽  
Author(s):  
Daniela Cilloni ◽  
Enrico Gottardi ◽  
Francesca Messa ◽  
Milena Fava ◽  
Patrizia Scaravaglio ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Scoring System ◽  
Quantitative Polymerase Chain Reaction ◽  
Risk Index ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Secondary Acute Myeloid Leukemia ◽  
Cell Percentage ◽  
Highly Correlated

Purpose: To determine whether pattern of WT1 gene expression is a useful marker for establishing prognosis and tracking disease progression in patients with myelodysplastic syndromes (MDS). Patients and Methods: We performed a quantitative assessment of the WT1 transcript amount by real-time quantitative polymerase chain reaction (RQ-PCR) in 173 samples (131 bone marrow samples and 42 peripheral-blood samples) from 131 patients with MDS (79 patients with refractory anemia [RA], 31 with RA with excess blasts [RAEB], 18 with secondary acute myeloid leukemia [s-AML] evolved from MDS, and three with deletion of 5q as the sole cytogenetic abnormality). Values obtained were correlated with the blast percentage and International Prognostic Scoring System (IPSS) score. Results: Sixty-five percent of BM and 78% of PB samples for RA and 100% of BM and PB samples of RAEB and s-AML expressed WT1 transcript amounts greater than the level observed in healthy volunteers. The degree of WT1 expression was highly correlated with the type of MDS, was much higher in RAEB and s-AML compared with RA, and increased during disease progression. Moreover, a significant correlation was found between WT1 expression levels, blast cell percentage, and the presence of cytogenetic abnormalities. Therefore, we found a significant correlation between the amount of WT1 transcripts and the IPSS score, which currently represents the most reliable risk index of disease progression available for MDS patients. Conclusion: WT1 is a useful molecular marker for risk assessment in MDS patients.

CD34-Positive Blast Count and p53 Expression in Bone Marrow Biopsies of Patients with Low-Risk Myelodysplastic Syndromes: Potential Predictive Tools of Response to Erythropoietin Stimulating Agents

Pathobiology ◽  
2021 ◽  
pp. 1-9
Author(s):  
Francesca Boggio ◽  
Alessandro Del Gobbo ◽  
Marco Barella ◽  
Giorgio Croci ◽  
Ramona Cassin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Therapeutic Option ◽  
P53 Protein ◽  
Low Risk ◽  
Histological Evaluation ◽  
Bone Marrow Biopsies ◽  
P53 Expression ◽  
Erythropoietin Stimulating Agents

<b><i>Introduction:</i></b> The first-line therapy for patients with low-risk myelodysplastic syndromes (MDSs) commonly consists of erythropoietin stimulating agents (ESAs), with a response rate ranging from 34 to 62%. For nonresponder patients, outside clinical trials, blood transfusions are the most frequent therapeutic option, with detrimental effect on the quality of life and with risks of iron-overload. Since no studies have been yet conducted on this topic, we investigated the potential predictive role of bone marrow (BM) histological evaluation in patients treated with ESAs. <b><i>Materials and Methods:</i></b> We performed a morphological and immunohistochemical retrospective analysis of BM biopsies of 96 patients with low-risk MDSs subsequently treated with ESAs. <b><i>Results:</i></b> In our series, substantial morphological overlap was found between responder and nonresponder patients. On the contrary, patients with a percentage of CD34-positive blasts &#x3e;3% or with p53 protein expression &#x3c;1% responded with a significantly higher frequency to ESAs. <b><i>Conclusions:</i></b> Our study reinforces the role of BM biopsy as diagnostic tool in MDSs, being also able to supply information related to response to ESAs and to its loss over time.

scholarly journals Safety and efficacy of azacitidine in elderly patients with intermediate to high-risk myelodysplastic syndromes

2016 ◽  
Vol 8 (1) ◽  
pp. 21-27 ◽  
Author(s):  
Shyamala C. Navada ◽  
Lewis R. Silverman
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Older Patients ◽  
Bone Marrow Failure ◽  
Common Adverse Effect ◽  
The United States ◽  
International Prognostic Scoring System ◽  
Hematopoietic Stem ◽  
Risk Of Death ◽  
Increased Risk

Myelodysplastic syndromes (MDS) represent a clonal hematopoietic stem cell disorder characterized by morphologic features of dyspoiesis, a hyperproliferative bone marrow, and one or more peripheral blood cytopenias. In patients classified according to the Revised International Prognostic Scoring System (R-IPSS) with intermediate or higher-risk disease, there is an increased risk of death due to progressive bone marrow failure or transformation to acute myeloid leukemia (AML). Azacitidine was the first DNA hypomethylating agent approved by the United States (US) Food and Drug Administration (FDA) for the treatment of MDS and the only therapy that has demonstrated a significant survival benefit over conventional care regimens (CCRs) in patients with intermediate or higher-risk disease. Prolonged survival is independent of achieving a complete remission. Azacitidine has been used in older patients with both clinical and hematological improvement as well as an acceptable side effect profile. The most common adverse effect is myelosuppression. These findings support the use of azacitidine as an effective treatment in older patients with higher-risk MDS.

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