Prognostic impact of gene mutations in myelodysplastic syndromes with ring sideroblasts

PURPOSE Patients with myelodysplastic syndromes (MDS) have a survival that can range from months to decades. Prognostic systems that incorporate advanced analytics of clinical, pathologic, and molecular data have the potential to more accurately and dynamically predict survival in patients receiving various therapies. METHODS A total of 1,471 MDS patients with comprehensively annotated clinical and molecular data were included in a training cohort and analyzed using machine learning techniques. A random survival algorithm was used to build a prognostic model, which was then validated in external cohorts. The accuracy of the proposed model, compared with other established models, was assessed using a concordance (c)index. RESULTS The median age for the training cohort was 71 years. Commonly mutated genes included SF3B1, TET2, and ASXL1. The algorithm identified chromosomal karyotype, platelet, hemoglobin levels, bone marrow blast percentage, age, other clinical variables, seven discrete gene mutations, and mutation number as having prognostic impact on overall and leukemia-free survivals. The model was validated in an independent external cohort of 465 patients, a cohort of patients with MDS treated in a prospective clinical trial, a cohort of patients with paired samples at different time points during the disease course, and a cohort of patients who underwent hematopoietic stem-cell transplantation. CONCLUSION A personalized prediction model on the basis of clinical and genomic data outperformed established prognostic models in MDS. The new model was dynamic, predicting survival and leukemia transformation probabilities at different time points that are unique for a given patient, and can upstage and downstage patients into more appropriate risk categories.

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Molecular Analysis of Myelodysplastic Syndrome with Isolated Del(5q) Reveals a Broad Spectrum of Clinically Relevant Mutations: A Study on 119 Patients and 26 Genes

Blood ◽

10.1182/blood.v124.21.4608.4608 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4608-4608

Author(s):

Manja Meggendorfer ◽

Tamara Alpermann ◽

Claudia Haferlach ◽

Susanne Schnittger ◽

Wolfgang Kern ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Specific Treatment ◽

Gene Mutations ◽

Gene Panel ◽

Prognostic Impact ◽

Treatment Needs ◽

Employment Equity ◽

Ring Sideroblasts ◽

Equity Ownership

Abstract Introduction: The WHO category of “Myelodysplastic syndrome with isolated del(5q)” shows a good prognosis. It also demonstrates sensitivity for specific treatment such as lenalidomide. However, in some patients it evolves to secondary AML. Underlying pathobiological mechanisms are still under debate. Aim: To determine the frequency of mutations in a 26 gene panel and to investigate a mutation pattern combined with clinical data and prognostic information. Patients and Methods: We investigated 119 patients (85 female, 34 male) having MDS with isolated del(5q), strictly classified according to WHO classification 2008 with respect to cytomorphology and cytogenetics (blasts below 5% in the bone marrow and 5q deletion sole). All patients underwent molecular analyses by a myeloid gene panel containing ASXL1, BCOR, BRAF, CBL, DNMT3A, ETV6, EZH2, FLT3-TKD, GATA1, GATA2, IDH1, IDH2, JAK2, KIT, NRAS, KRAS, MPL, NPM1, PHF6, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1, and WT1. The library was generated with the ThunderStorm (RainDance Technologies, Billerica, MA) and sequenced on a MiSeq instrument (Illumina, San Diego, CA). Results: Most patients harbored 1 mutation (60/119, 50%), while 2, 3, and 4 mutations per patient occurred less frequently (18/119, 15%; 2/119, 2%; and 1/119, 1%, respectively). In 38/119 patients (32%) no gene mutation was identified in addition to the del(5q). In the total cohort the most frequently mutated genes were DNMT3A and TP53 (21/119, 18% each), followed by SF3B1 (20/119, 17%), TET2 (14/119, 12%), ASXL1 (9/119, 8%), and JAK2 (7/119, 6%). Although these 6 gene mutations overlapped rarely and occurred frequently as sole mutations, they were not completely mutually exclusive. The mutation frequencies of all other analyzed genes were below 5%. Dividing the patients in groups defined by a bone marrow blast count of <2% and 2-5%, as described in IPSS-R, we could not detect any correlation to the mutation number per patient. However, patients that had no mutation were younger compared to patients with at least 1 mutation (70 vs. 76 years, p=0.009). But there was no difference between these 2 patient groups in white blood cell count, hemoglobin level, or platelet count. Taking single genes into account revealed that TP53 and SF3B1 mutations (mut) correlated with higher age (78 vs. 73 years, p=0.047; 78 vs. 73 years, p=0.050, respectively). Addressing the correlations of ring sideroblasts (RS) >15% and SF3B1mut showed that also in MDS with isolated del(5q) these two parameters significantly correlate with a mean of 19% RS (range: 0-80%) in SF3B1mut and only 1% RS in SF3B1 wildtype patients (wt; range: 0-12%, p<0.001). Looking at prognostic relevance of gene mutations surprisingly showed that SF3B1mut patients had a significantly worse outcome than SF3B1wt patients (median overall survival (OS) 31 vs. 91 months, p=0.008). Comparing the mutation frequency of TP53 in MDS with isolated del(5q) with all other MDS (Haferlach et al, Leukemia 2014) resulted in a significant higher mutation rate in MDS with isolated del(5q) (21/119 (18%) vs. 49/781 (6%), p<0.001). However, we did not find a prognostic impact of TP53mut in our cohort. Our patients were unselected and median OS was 91 months. Thus, our cohort may include a larger proportion of patients earlier in their clinical course compared to cohorts enrolled in treatment studies. Therefore the negative impact of TP53mut may become obvious later or even not before treatment needs to be started. Of note, 50% (60/119) of our patients were only under observation or received red blood cells or erythropoietin only. In contrast, an increasing number of gene mutations per patient showed a very strong trend towards a worse outcome with a median OS of 90 months in patients with no or 1 additional mutation in comparison to patients with more than 1 mutation (median OS: 36 months, p=0.061). Conclusion: 1) In myelodysplastic syndrome with isolated del(5q) the 5 most frequently mutated genes are comparable to all other MDS (Haferlach et al, Leukemia 2014). 2) In contrast, TP53 is more frequently mutated in MDS with isolated del(5q). 3) Ring sideroblasts >15% correlate with SF3B1mut. 4) SF3B1mut lead to significantly worse OS. 5) Increasing numbers of mutations show negative prognostic impact. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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ASXL1 Mutations in Myelodysplastic Syndromes with 1% or More Ring Sideroblasts: Prevalence, Clinical Correlates and Prognostic Relevance

Blood ◽

10.1182/blood.v126.23.2882.2882 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2882-2882

Author(s):

Naseema Gangat ◽

Terra L. Lasho ◽

Mrinal M Patnaik ◽

Christy Finke ◽

Mark R Litzow ◽

...

Keyword(s):

Median Survival ◽

Myelodysplastic Syndromes ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Refractory Anemia ◽

Prognostic Impact ◽

Wild Type ◽

Monosomy 7 ◽

Clinical Correlates ◽

Ring Sideroblasts

Abstract Background: Addition of sex combs-like 1 (ASXL1) is frequently mutated (mutational frequency 14-29%) and is prognostically relevant in myelodysplastic syndromes (MDS) (Bejar, NEJM 2011, Thol, JCO 2011). The prevalence and prognostic impact of ASXL1 mutation in MDS with ring sideroblasts (MDS-RS) is not known. MDS-RS is defined by the presence of ≥15% RS in bone marrow (BM), with refractory anemia with ring sideroblasts (RARS) being the prototype but may also be seen in other categories. Methods : Our institutional database was reviewed to identify patients with WHO-defined primary MDS with ≥1% BM RS. Pathology slides, including iron stains, were reviewed to accurately quantify BM RS percentage and confirm WHO morphologic categories. All patients were annotated for their mutational status including ASXL1, JAK2, MPL and IDH with a subset for SF3B1 by PCR sequencing performed on BM specimens obtained at diagnosis. Results : i) Patient characteristics: A total of 76 MDS patients displayed ≥1% BM RS (median age 72 years; 76% males); 51 (67%) patients had ≥15% BM RS. IPSS-R risk categories for the entire 76 study patients were 30% very low, 37% low, 14% intermediate, 11% high and 8% very high; IPSS-R karyotype was normal in 63%, very good/good risk 17%, intermediate risk 12%, and poor/very poor in 8%; 3% had monosomal karyotype. ii) Prevalence of ASXL1 mutations: Twenty-one (28%) of the 76 study patients were ASXL1 mutated; ASXL1 mutational frequencies were 25% (16/63 patients) in the absence and 38% (5/13 patients) in the presence of excess blasts (P =0.34). When considering only those patients with ≥15% BM RS (n =51), ASXL1 mutations were detected in 12 (24%) patients with mutational frequencies of 24% (11/46 patients) in the absence and 20% (1/5 patients) in the presence of excess blasts (P =0.84); ASXL1 mutational frequencies were 13% (3/23 patients) in RARS and 37% (7/19 patients) in RCMD-RS (P=0.07). In terms of other mutations, all 76 study patients were wild-type for JAK2 and MPL, whereas IDH2 R140Q mutations were present in 4 (5%) patients, including 3 with concomitant ASXL1 and IDH2 mutations. IDH1 mutation was seen in only 1 patient. 25 of 43 (58%) patients screened were mutated for SF3B1, including 4 (9%) who were mutated for both ASXL1 and SF3B1. Significant associations were evident between ASXL1 and IDH2 mutations (P =0.02) but not between ASXL1 and SF3B1 mutations (P =0.61). iii) Clinical correlates of ASXL1 mutations: Among all 76 study patients, presence of ASXL1 mutation did not correlate with age (P =0.30), hemoglobin level (P =0.17), platelet count (P =0.53), BM blast percentage (P =0.17), WHO morphologic category (P =0.34), transfusion dependence (P =0.84), IPSS-R cytogenetic categories (P =0.93), or IPSS-R risk group (P =0.33). The results were unchanged when analyzing the 51 patients with MDS-RS (i.e. ≥15% BM RS). Amongst the ASXL1 mutated patients (n =21) IPSS-R cytogenetic categories were as follows: 13 patients with normal karyotype (62%), 2 patients with trisomy 8 (10%), 1 patient each with -Y, del(11q), del(5q), del(20q), isochromosome 17 and monosomy 7 (5% each). iv) Prognostic impact of ASXL1 mutations: Median follow-up was 42.5 months, during which time 69 (91%) deaths and 8 (11%) leukemic transformations were documented. ASXL1 mutated patients had a median survival of 29 months, compared to 45 months in ASXL1 wild-type patients (P =0.04). However, the difference in median survival was no longer significant during multivariable analysis, which instead identified only IPSS-R and transfusion need as being independent predictors of inferior survival. Amongst those patients without excess blasts (n =63), presence of ASXL1 mutation predicted inferior survival in univariate analysis (P =.04) and significance was sustained during multivariable analysis that included IPSS-R cytogenetic categories (P =.04) but became borderline when WHO morphologic category was included (P =0.06); ASXL1 mutated patients had a shortened median survival of 43 months compared to 66 months in ASXL1 wild-type patients (P =.04). In the presence of ≥15% BM RS, ASXL1 mutations did not affect survival (P =0.48); the results were the same for RARS (P =0.9) and RCMD-RS (P =0.64). Conclusions : ASXL1 mutations might not affect survival in MDS patients with ≥15% BM RS, including those with RARS or RCMD-RS. Furthermore, an apparent survival disadvantage seen in ASXL1 -mutated MDS patients with ≥1% BM RS was accounted for by IPSS-R. Disclosures Pardanani: Stemline: Research Funding.

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Prognostic impact of ASXL1 mutations in patients with myelodysplastic syndromes and multilineage dysplasia with or without ring sideroblasts

Leukemia Research ◽

10.1016/j.leukres.2018.07.010 ◽

2018 ◽

Vol 71 ◽

pp. 60-62 ◽

Cited By ~ 8

Author(s):

Abhishek A. Mangaonkar ◽

Naseema Gangat ◽

Aref Al-Kali ◽

Michelle A. Elliott ◽

Kebede H. Begna ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Prognostic Impact ◽

Multilineage Dysplasia ◽

Ring Sideroblasts

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Reclassifying myelodysplastic syndromes: what's where in the new WHO and why

Hematology ◽

10.1182/asheducation-2015.1.294 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 294-298 ◽

Cited By ~ 27

Author(s):

Daniel A. Arber ◽

Robert P. Hasserjian

Keyword(s):

Advisory Committee ◽

Diagnostic Criteria ◽

Myelodysplastic Syndromes ◽

Who Classification ◽

Prognostic Significance ◽

Gene Mutations ◽

Refractory Anemia ◽

Ring Sideroblasts ◽

Actual Publication

Abstract A revision to the 4th edition of the WHO Classification of myelodysplastic syndromes (MDSs), originally published in 2008, is expected in mid-2016. Based on recommendations of a Clinical Advisory Committee, the revision will aim to incorporate new discoveries in MDS that impact existing disease categories. Although the basic diagnostic principles of the WHO classification remain unchanged, several changes to the classification are proposed. All revisions are considered preliminary until the actual publication of the monograph and online document. Proposals for change include abandoning the routine use of “refractory anemia/cytopenia” in the various disease names, including the prognostic significance of gene mutations in MDS, revising the diagnostic criteria for MDS entities with ring sideroblasts based on the detection of SF3B1 mutations, modifying the cytogenetic criteria for MDS with isolated del(5q), reclassifying most cases of the erythroid/myeloid type of acute erythroleukemia, and recognizing the familial link in some cases of MDS. This review will provide details of the major proposed changes as well as rationale for the revisions.

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