The heterogeneous prognosis of patients with myelodysplastic syndrome and chromosome 5 abnormalities

Kantarjian, Hagop M.; O’Brien, Susan; Ravandi, Farhad; Borthakur, Gautam; Faderl, Stefan; Bueso‐Ramos, Carlos E.; Abruzzo, Lynne V.; Pierce, Sherry; Shan, Jianqin; Issa, Jean–Pierre J.; Garcia‐Manero, Guillermo

doi:10.1002/cncr.24575

Cited by 39 publications

(20 citation statements)

References 36 publications

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“…We analyzed the outcome of patients with MDS and alteration of chromosome 5. 30 In this series, 18% of 2743 patients had alterations of chromosome 5. Patients without a chromosome 5 alteration had a survival of 17 months; for those with deletion 5q it was 9 months; and for those with monosomy 5 it was 6 months.…”

Section: Molecular Alterations With Prognostic Value In Mds: Not Onlymentioning

confidence: 66%

Prognosis of Myelodysplastic Syndromes

Garcia-Manero

2010

Hematology

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The myelodysplastic syndromes (MDS) are a very complex group of hematopoietic disorders. The degree of complexity relates not only to the intrinsic pathobiological characteristics of the disease, but also to the group of patients whom it affects most frequently: older individuals or those who have been exposed to prior forms of chemotherapy. It is therefore crucial to develop clinical tools to predict with a certain degree of precision the prognosis and outcome for patients with specific subtypes of MDS in specific clinical situations. At the present time, patients with MDS are diagnosed using a set of well-established histopathological criteria. Prognosis is established using classifications that include morphological features, percentage of blasts, and clinical and molecular characteristics such as peripheral cytopenias and cytogenetics. The International Prognostic Scoring System (IPSS) is a classic example of this type of classification. Over the last 5 years, there has been an intense effort to develop new prognostic systems for MDS, and new molecular alterations with potential prognostic value have been discovered. Over the same period of time, several new therapeutic interventions have been developed for patients with MDS. Biomarkers of response to these agents, in particular for the hypomethylating agents, are needed to predict clinical benefit. This review summarizes current prognostic models of MDS and new molecular alterations with potential prognostic potential.

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Section: Molecular Alterations With Prognostic Value In Mds: Not Onlymentioning

confidence: 66%

Prognosis of Myelodysplastic Syndromes

Garcia-Manero

2010

Hematology

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“…The prognosis of MDS patients with del(5q) depends on various factors including additional chromosome abnormalities, [35][36][37] but lenalidomide exerts a favorable effect on 5q-MDS patients with complex abnormalities similarly as the patients with isolated del(5q) or to a lesser degree. 35,38,39 Our basic study might provide potentially useful issues to explain the clinical efficacy of lenalidomide on the patients with del(5q) and additional abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis

et al. 2010

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Myelodysplastic syndromes (MDS) are a group of hematopoietic stem cell disorders characterized by refractory cytopenias and susceptibility to leukemic transformation. On a subset of MDS patients with deletion of the long arm of chromosome5 (del(5q)), lenalidomide exerts hematological and cytogenetic effects, but the underlying pharmacological mechanisms are not fully understood. In this study, we have investigated the in vitro effects of lenalidomide on an MDS-derived cell line, MDS-L, which carries del(5q) and complex chromosome abnormalities. We found that the growth of MDS-L cells was specifically suppressed mainly by apoptosis, and in addition, multinucleated cells were frequently formed and finally died out in the presence of lenalidomide. Time-lapse microscopic observation and the DNA ploidy analysis revealed that lenalidomide does not affect DNA synthesis but inhibits cytokinesis of MDS-L cells. The gene expression profile showed decreased expression of M phase-related genes such as non-muscle myosin heavy-chain 10, polo-like kinase 1, aurora kinase B, citron kinase and kinesin family member 20A(KIF20A). Interestingly, KIF20A is located at 5q31. These data contribute to the understanding of action mechanisms of lenalidomide on MDS with del(5q) and complex abnormalities.

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“…6 These studies indicate that the prognosis of patients with lower-risk del(5q) MDS is less favorable than previously considered, and that factors other than IPSS classification have an impact on patients' outcomes. [7][8][9] Molecular mutations, including TP53 mutations, are emerging as independent prognostic factors. 8 Using deep-sequencing technology, 18% of patients with lower-risk del(5q) MDS were found to have TP53 mutated subclones which rendered them at higher risk of progression.…”

Section: Introductionmentioning

confidence: 99%

p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o nchemistry (IHC) has been used as a surrogate marker for TP53 gene mutations in hematologic and other malignancies, including large B-cell lymphoma. [22][23][24] Recently, it was demonstrated that p53 nuclear expression correlated with hemizygous TP53 mutation and outcomes in relapsed myeloma patients treated with lenalidomide. 25 AML following MDS has a dismal prognosis, which makes prediction essential, especially in patients who potentially could be cured by stem cell transplantation. In order to develop a clinically useful prognostic tool, we measured p53 protein expression by IHC in a cohort of 85 patients with lower-risk del(5q) MDS from the MDS-004 clinical trial, and compared outcomes and responses to lenalidomide treatment in patients with respect to strong nuclear p53 expression. We demonstrate the independent prognostic value of p53 IHC in this population of patients, and show that strong nuclear staining reflects underlying TP53 mutations. Our findings underscore the importance of including molecular markers such as TP53 mutations in risk-assessment for del(5q) MDS patients. Methods PatientsFormalin-fixed paraffin-embedded BM trephines from patients enrolled in the phase III, randomized, double-blind, placebo-controlled MDS-004 trial were retrieved. 5 The MDS-004 trial assessed the efficacy and safety of lenalidomide in 205 red blood cell transfusion-dependent patients with low-or intermediate-1-risk del(5q) MDS. The inclusion criteria and treatment schedule were as previously described; 5 a bone marrow biopsy was recommended, but not mandatory. The present study was conducted under the ethical consent for the MDS-004 trial. The original ethical permit did not include any type of sequencing; therefore, TP53 deep-sequencing analysis was only possible in a subset of patients who were still alive and provided consent to an ethical permit obtained after the MDS-004 trial had been completed. In Sweden, gene-sequencing analysis was performed under a separate national ethical permit, which was used for the pyrosequencing of laser-microdissected BM cells. Bone marrow morphology and immunohistochemistryOverall, 131 BM trephines from 85 of the 205 patients (41%; IHC study cohort) obtained at baseline and follow-up were assessed in a blinded fashion. Serial BM biopsies were available for 25% (21 of 85) of the patients. BM cellularity and fibrosis were assessed according to European consensus guidelines. 26 The percentage and intensity of p53 staining was assessed based on a total manual count of 1000 BM hematopoietic cells (lymphocytes/lymphoid aggregates excluded) and graded as: 0 (negative); 1+ (weakly positive); 2+ (moderately positive); and 3+ (strongly positive). The entire BM trephine was also assessed using a Modified Quick Score; 27 a score of ≥3 was used to define p53-positive staining as previously described. 28 In addition, all samples were assessed blindly for the percentage of p53-DO1 strongly positive (3+) cells by three hematopathologists fro...

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The heterogeneous prognosis of patients with myelodysplastic syndrome and chromosome 5 abnormalities

Cited by 39 publications

References 36 publications

Prognosis of Myelodysplastic Syndromes

Prognosis of Myelodysplastic Syndromes

Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis

p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

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