SF3B1 Mutations Are Associated with Favorable Cytogenetics in Patients with Myelodysplastic Syndromes with Ring Sideroblasts

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3823-3823 ◽  
Author(s):  
Vincent-Philippe Lavallée ◽  
David Faucher ◽  
Bruno Lamontagne ◽  
Josée Hébert ◽  
Lambert Busque
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
World Health ◽  
Refractory Anemia ◽  
Wild Type ◽  
Event Free Survival ◽  
Free Survival ◽  
Mutational Hotspots ◽  
Ring Sideroblasts ◽  
Bone Marrow Blasts

Abstract Abstract 3823 Background: Somatic mutations of splicing factor 3B, subunit 1 (SF3B1) are prevalent in myelodysplastic syndromes (MDS) with ring sideroblasts (RS). Little is known about the clinical phenotype associated with these mutations. Initial studies have reported an excellent event-free survival (EFS) in patients with SF3B1 mutations but subsequent reports did not confirm that observation. Therefore, its clinical significance remains uncertain. Our objective was to determine if the SF3B1 mutational status predicts distinctive morphological, cytogenetic or clinical characteristics in patients with MDS with RS. Methods and patients: Twenty-seven patients diagnosed with MDS and ≥ 15% RS in bone marrow aspiration between 2000 and 2011 at our institution and other hospitals affiliated to the Quebec Leukemia Cell Bank (BCLQ) and with available material for genetic analyses were included in this study. Morphology of samples was revised. After DNA extraction, polymerase chain reaction was performed to amplify SF3B1 mutational hotspots in exons 13 to 15. Amplicons were sequenced by the Sanger method. Clinical and laboratory data were collected retrospectively from hospital medical records and BCLQ database. Results: Point mutations of SF3B1 were found in 48% (13/27) with the following distribution: refractory anemia with RS (RARS): 7/10, refractory cytopenia with multilineage dysplasia (RCMD): 5/10 and refractory anemia with excess blasts (RAEB): 1/7. All mutations were heterozygous nonsense mutations and K700E exon 15 mutations accounted for 85% (11/13) of mutations. The remaining mutations were located in exon 14 at position 666. In the entire cohort, SF3B1 mutations were associated with an older median age at diagnosis (69 vs 60 years, p= 0.007). They were associated with favorable cytogenetics whereas unmutated SF3B1 was associated with unfavorable cytogenetics (8 cases vs 0 with favorable cytogenetics and 0 cases vs 11 with unfavorable cytogenetics for mutated and wild type SF3B1 respectively, p < 0.0001). Median overall survival (OS) was similar in the 2 groups (not reached vs 27 months, p=0.7) but median EFS was higher in patients with mutated SF3B1 (not reached vs 5 months, p=0.02). To evaluate the influence of higher bone marrow blasts on outcomes, analyses were restricted to the RARS and RCMD-RS categories. In that subgroup, SF3B1 mutations were correlated with higher median platelet counts at diagnosis (201 vs 70 × 109/L, p=0,04). In addition, SF3B1 mutations remained associated with favorable cytogenetics, and unmutated SF3B1 with unfavorable cytogenetics (p=0.004). Moreover, SF3B1 mutations were more frequently detected within favorable or intermediate-1 categories of the International Prognostic Scoring System (IPSS) compared to wild type SF3B1 (p=0.04). However, in patients with < 5% bone marrow blasts, EFS was similar between mutated and unmutated SF3B1 (not reached vs 46 months, p =0.4). Conclusion: In this series, SF3B1 mutations are frequent in MDS with RS and they are strongly associated with favorable cytogenetics. They are mostly detected among low-risk groups of the World Health Organisation classification (RARS and RCMD-RS), but they are not independently associated with an increased overall or event-free survival. Disclosures: No relevant conflicts of interest to declare.

SF3B1 Mutations Are Prevalent in Myelodysplastic Syndromes with Ring Sideroblasts but Do Not Hold Independent Prognostic Value

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 460-460 ◽  
Author(s):  
Mrinal M. Patnaik ◽  
Terra L Lasho ◽  
Janice M Hodnefield ◽  
Ryan A Knudson ◽  
Rhett P Ketterling ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Prognostic Value ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
World Health ◽  
Refractory Anemia ◽  
Ring Sideroblasts ◽  
Risk Categories ◽  
Good Risk

Abstract Abstract 460 Background: SF3B1 mutations were recently reported to occur in myelodysplastic syndromes (MDS), especially in the presence of ring sideroblasts (RS) (Papaemmanuil et al. Leukemia Research 2011, Volume 35, Supplement 1, page S18). We sought to accurately define the interaction between SF3B1 mutations, bone marrow morphology, karyotype and prognosis in MDS with ≥15% RS (MDS-RS). Methods: Mayo Clinic databases and cell banks were queried to identify patients with MDS and ≥15% RS (MDS-RS). All study patients were required to have undergone bone marrow examination and cytogenetic evaluation at diagnosis. Pathology slides, including iron stains, were centrally re-reviewed to accurately quantify bone marrow RS percentage and confirm World Health Organization (WHO) morphologic categories. Detailed analysis of clinical and cytogenetic parameters was performed to risk stratify patients according to the revised International Prognostic Scoring System (IPSS-R) (Greenberg et al. Leukemia Research 2011, Volume 35, Supplement 1, page S6). All patients were annotated for their mutational status involving JAK2, MPL and IDH. PCR sequencing was used to identify SF3B1 mutations. Results I: Baseline patient information: The study is currently ongoing; to date, results are availab1e in 88 patients (median age 72 years, 69% males) including 36 (41%) patients with refractory anemia with RS (RARS), 36 (41%) with refractory cytopenia with multilineage dysplasia and ≥15% RS (RCMD-RS), 11 (12%) with refractory anemia with excess blasts (RAEB)-1 and ≥15% RS (RAEB1-RS) and 5 (6%) with RAEB2-RS. Median (range) values were 9.1 g/dL (5.8–15.7) for hemoglobin, 4.1 × 109/L (1.2–35.2) for leukocytes and 164 × 109/L (6–585) for platelets. IPSS-R risk categories were 20% very good, 49% good, 11% intermediate, 3% poor and 16% very poor. Karyotype was normal in 60%, other very good/good risk 16%, intermediate-risk 2%, and poor/very poor in 22%; 14% had monosomal karyotype (MK). Six (7%), four (5%) and zero (0%) patients displayed IDH, JAK2 or MPL mutations. Red cell transfusion need was documented in 27 (31%) patients. Results II: Prevalence and distribution of SF3B1 mutations and clinical correlates: SF3B1 mutations (all heterozygous) were detected in 40 (∼46%) of all 88 study patients: 25 (63%) K700E, 6 (15%) K666N/Q/R, 3 (8%) E622D, 2 (5%) H662D/Q, 2 (5%) Y623C, 1 (3%) R625C, and 1 (3%) T663I. One patient each displayed both SF3B1K700E and IDH2R140Q or SF3B1K700E and JAK2V617F. SF3B1 mutational frequencies were 69% for RARS, 36% for RCMD-RS, 18% for RAEB1-RS and 0% for RAEB2-RS (p=0.0007). SF3B1 mutations clustered with normal (59%) and other very good/good risk (57%) karyotype and were infrequent in poor/very poor karyotype (5%; p=0.0004). Additional significant correlations were noted between SF3B1 mutations and lower IPSS-R risk category (p=0.0004), advanced age (p=0.006), higher platelet count (p=0.0003). Results II: SF3B1 mutations and prognostic relevance in MDS-RS: To date, 68 (∼77%) deaths and 10 (∼11%) leukemic transformations have been documented. Median follow-up for living patients was 82 months. Univariate survival analysis considering all 88 study patients identified the following as strongly significant risk factors: IPSS-R (p<0.0001), WHO morphologic categories (p<0.0001), cytogenetic risk categories (p<0.0001), and transfusion need (p=0.0003). In multivariable analysis, only IPSS-R and transfusion need remained significant. In univariate analysis, the presence of SF3B1 mutations was significantly associated with better overall (p=0.04) and leukemia-free (p=0.03) survival; however, in both instances, significance was completely accounted for by WHO morphologic risk categorization and the morphology-adjusted p values were 0.6 and 0.2, respectively. In other words, when RARS and RCMD were analyzed separately, there was no additional prognostic value from the presence or absence of SF3B1 mutations (Figures 1 and 2; p=0.67 and 0.44, respectively). Conclusions: SF3B1 mutations are prevalent in RARS and RCMD-RS but do not provide additional, WHO morphology-independent or IPSS-R-independent, prognostic information. Disclosures: No relevant conflicts of interest to declare.

Prognostic Irrelevance of Ring Sideroblast Percentage in World Health Organization Defined Myelodysplastic Syndromes without Excess Blasts,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3803-3803
Author(s):  
Mrinal M. Patnaik ◽  
Curtis A Hanson ◽  
Nanna Sulai ◽  
Janice M Hodnefield ◽  
Ryan A Knudson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Prognostic Scores ◽  
World Health ◽  
Refractory Anemia ◽  
Ring Sideroblasts ◽  
Red Cell Transfusion ◽  
Health Organization ◽  
Risk Categories

Abstract Abstract 3803 Background: Ring sideroblasts (RS) represent abnormal mitochondrial iron deposits that are commonly present in myelodysplastic syndromes (MDS). The presence of ≥15% RS, by definition (World Health Organization-WHO) is necessary for a diagnosis of a MDS-RS; with refractory anemia with ring sideroblasts (RARS) being a specific morphologic category. RS can also be seen with other morphologic categories such as; refractory cytopenias with multilineage dysplasia (RCMD), MDS-unclassifiable (MDS-U) and refractory anemia with excess blasts (RAEB-1/2). Amongst these categories, RARS is generally believed to have the best survival rate with the lowest risk of leukemic transformation and this has been attributed to the absence of associated dysplasia in more than one lineage. However, it has not been systematically shown whether or not the exact percentage of RS provides additional prognostic information in the context of an accurate morphologic categorization and risk stratification by karyotype or the revised IPSS (IPSS-R). Methods: 200 patients with primary MDS without excess blasts and ≥1% RS were seen at the Mayo Clinic from 1997 through 2007. All patients underwent bone marrow (BM) examination and cytogenetic evaluation at diagnosis and the pathology slides, including iron stains, were centrally re-reviewed to accurately quantify bone marrow (BM) RS percentage and to confirm WHO morphologic categories. Molecular profiling included analysis for IDH1, IDH2, JAK2 and MPL mutations. For the purposes of this study patients were divided into 4 categories based on the RS percentage; <5%, 5–14%, 15–50% and >50%. In addition, each patient was assigned IPSS and IPSS-R prognostic scores at diagnosis and risk stratified by karyotype according to the IPSS-R cytogenetic risk categories. Cox proportional regression method was used for multivariable analysis. Results: Of the overall 200 study patients, 140 (70%) were male and median age was 71 years (range, 17–90 years). At presentation, 34 (17%) patients were red cell transfusion-dependent. There were 56 (28%) patients with <5% RS (RCMD-52, MDS-U-14), 32 (16%) with 5–14% RS (RCMD-29, MDS-U-3), 79 (39%) with 15–50% RS (RARS-43, RCMD-29, MDS-U-2) and 33 (16%) with >50% RS (RARS-13, RCMD-17, MDS-U-3). Three patients (2%) were IDH1 mutant (RARS-1, RCMD-2), 17 (8%) IDH2 mutant (RARS-1, RCMD-14, MDS-U-2), 5 JAK2 V617F (3%) mutant (RARS-2, RCMD-3) and one patient with RCMD had the MPL W515L mutation. At a median follow-up of 33 months, 156 (73%) deaths and 24 (12%) leukemic transformations were documented. Median survivals were 63 months for MDS with >50% RS, 43 months for MDS with 15–50% RS, 35 months for MDS with 5–14% RS, and 14 months for MDS with <5% RS (p=0.005). In univariate analysis, additional risk factors included decreased hemoglobin, decreased platelet count, increased circulating blasts, WHO morphologic categories, red cell transfusion need, IPSS, IPSS-R and cytogenetic risk categories per IPSS-R. On a multivariable analysis only the IPSS-R prognostic score (p<0.0001) and the WHO morphologic categories (p=0.02 for RARS) retained significance. Univariate analysis disclosed significantly inferior leukemia-free survival (LFS) in patients with RCMD, thrombocytopenia, increased circulating blasts, and poor IPSS and IPSS-R prognostic scores. On multivariable analysis once again only the IPSS-R prognostic scores (p=0.02) and WHO morphologic categories (p=0.02) retained their significance. In other words, RS percentage, independent of WHO classification, as a continuous or categorical variable (i.e.: <5%, 5–14%, 15–50% & >50%) did not affect either overall survival or LFS. Conclusions: In MDS without excess blasts, once an accurate WHO morphologic categorization is made based on the presence or absence of multi-lineage dysplasia, there is no additional prognostic value for quantifying bone marrow ring sideroblasts. WHO classification and IPSS-R prognostic scores remain the most important factors in assessing patients with MDS. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽  
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.

scholarly journals SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value

Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 569-572 ◽  
Author(s):  
Mrinal M. Patnaik ◽  
Terra L. Lasho ◽  
Janice M. Hodnefield ◽  
Ryan A. Knudson ◽  
Rhett P. Ketterling ◽  
...  
Keyword(s):  
World Health Organization ◽  
Myelodysplastic Syndromes ◽  
Prognostic Value ◽  
Univariate Analysis ◽  
World Health ◽  
Refractory Anemia ◽  
Multilineage Dysplasia ◽  
Ring Sideroblasts ◽  
Health Organization ◽  
Risk Categorization

SF3B1 mutations were recently reported in myelodysplastic syndromes (MDSs), especially in the presence of ring sideroblasts (RSs). We sought to define the interaction between SF3B1 mutations, morphology, karyotype, and prognosis in MDS with more than or equal to 15% RS (MDS-RS). We studied 107 patients with MDS-RS, including 48 with refractory anemia with RS (RARS), 43 with refractory cytopenia with multilineage dysplasia (RCMD)-RS, 11 with refractory anemia with excess blasts-1 (RAEB1)–RS, and 5 with RAEB2-RS. SF3B1 mutations were detected in 53 (∼ 50%) patients: 35 RARS (73%), 16 RCMD-RS (37%), and 2 RAEB1-RS (18%). In univariate analysis, the presence of SF3B1 mutations was associated with better overall (P < .01) and leukemia-free (P < .01) survival; however, in both instances, significance was completely accounted for by World Health Organization morphologic risk categorization. In other words, when RARS and RCMD-RS were analyzed separately, there was no additional prognostic value from the presence or absence of SF3B1 mutations.

scholarly journals Prognostic irrelevance of ring sideroblast percentage in World Health Organization–defined myelodysplastic syndromes without excess blasts

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5674-5677 ◽  
Author(s):  
Mrinal M. Patnaik ◽  
Curtis A. Hanson ◽  
Nanna H. Sulai ◽  
Janice M. Hodnefield ◽  
Ryan A. Knudson ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Multivariable Analysis ◽  
World Health ◽  
Refractory Anemia ◽  
Idh Mutations ◽  
Ring Sideroblasts ◽  
Transfusion Dependency ◽  
Health Organization ◽  
The Impact

Abstract The presence of ≥ 15% bone marrow (BM) ring sideroblasts (RS) and < 5% blasts is required for a diagnosis of refractory anemia with ring sideroblasts. We examined the phenotypic and prognostic relevance of this “15%” RS threshold in 200 patients with myelodysplastic syndromes (MDS) without excess blasts and with ≥ 1% RS. The impact of RS% was assessed both as a continuous and categorical variable: < 5% (n = 56), 5%-14% (n = 32), 15%-50% (n = 79), and > 50% (n = 33). RS% correlated (P < .05) directly with age, platelet count, transfusion dependency, BM cellularity, and mutant SF3B1 and inversely with hemoglobin level, multilineage dysplasia, and high-risk karyotype; but did not correlate with IDH mutations. At a median follow-up of 33 months, 156 (73%) deaths and 24 (12%) leukemic transformations were documented. Neither univariate nor multivariable analysis showed significant effect for RS% on overall or leukemia-free survival, suggesting the limited prognostic value of quantifying BM RS in MDS.

Considering Bone Marrow Blasts from Nonerythroid Cells Improves the Prognostic Evaluation of Myelodysplastic Syndromes with Ring Sideroblasts

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1991-1991
Author(s):  
Leonor Arenillas ◽  
Xavier Calvo ◽  
Elisa Luño ◽  
Leonor Senent ◽  
Ester Alonso ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Conflicts Of Interest ◽  
Refractory Anemia ◽  
Prognostic Impact ◽  
Cox Regression Analysis ◽  
Prognostic Evaluation ◽  
Kaplan Meier ◽  
Ring Sideroblasts ◽  
Bone Marrow Blasts

Abstract Introduction: As showed in a recent study of our group, considering bone marrow (BM) blasts from nonerythroid cellularity (NECs) improves the prognostic evaluation of MDS (Arenillas et al, J Clin Oncol 2016). By enumerating blasts from NECs, 12% of MDS patients diagnosed within WHO categories with less than 5% BM blasts were reclassified into higher-risk categories and showed a poorer overall survival than did those who remained in the initial categories. Refractory anemia with ring sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) have shown an special good outcome in different studies. As MDS with ring sideroblasts (MDS-RS) usually present a high percentage of BM erythroblasts, considering BM blasts from NECs could imply a risk overestimation of this subset of patients. Aim: we evaluated the relevance of considering BM blasts from NECs or from total nucleated cells (TNCs) on classification and prognostication of the group of patients diagnosed with MDS-RS. Methods: We retrospectively analyzed 3,924 de novo MDS diagnosed according to WHO 2001 and 2008 classifications from the MDS Spanish registry. 1,045 patients presented less than 5% BM blasts from TNCs and equal or greater than 15% BM ring sideroblasts, fulfilling current definition for RARS (WHO 2001 and 2008) and RCMD-RS (WHO 2001). Moreover 1,233 patients with equal or greater than 5% BM ring sideroblasts and less than 5% BM blasts were analyzed in order to explore the future definition of WHO 2016, that considered as MDS-RS those patients with 5%-<15% BM ring sideroblasts if SF3B1 mutation is present. This was a tentative analysis since SF3B1 mutation information was not available in our series. Percentage of BM blasts from NECs was calculated as follows: [%BM blasts from TNCs/(100 - %BM erythroblasts) x 100]. Survival curves were constructed by using the Kaplan-Meier method and compared using the log-rank test. Univariable and multivariable Cox regression analysis were also implemented. Results: Median age at diagnosis of MDS-RS was 76y (25-101) and 59% were males. Estimated median follow-up, as calculated by reverse Kaplan-Meier method, was 50.1 months (95% CI, 45.5-54.7) and median OS was 96.5 months. By enumerating blasts from NECs, 10% of MDS-RS patients were reclassified into categories with equal or greater than 5% BM blasts and showed a poorer overall survival (OS) than did those who remained in initial categories (median OS, 68.1 vs 97.6 months, P=0.025; Hazard ratio (HR): 1.41; 95%CI: 1.04-1.91; p=0.026). After adjusting the survival analysis by IPSS cytogenetic risk groups, the prognostic impact of BM blasts considered from NECs maintained its significance (HR: 1.37; 95%CI: 1.01-1.85; p=0.045). Similar results were observed applying this method to the group of MDS patients with equal or greater than 5% BM ring sideroblasts and less than 5% BM blasts. By considering blasts from NECs, 10% of this subset of patients were reclassified into categories with equal or greater than 5% BM blasts and showed a poorer OS than did those who remained in initial categories (median OS, 60.2 vs 85.8 months, P=0.003; HR: 1.51; 95%CI: 1.15-1.97; p=0.003; HR adjusted for IPSS cytogenetics: 1.46; 95%CI: 1.12-1.92; p=0.006). Conclusion: considering bone marrow blasts from nonerythroid cells improves the prognostic evaluation of MDS with ring sideroblasts. Written on behalf of the Grupo Español de Síndromes Mielodisplasicos (GESMD). Disclosures No relevant conflicts of interest to declare.

Outcome Of Patients With Myelodysplastic Syndrome (MDS) With Bone Marrow Blasts Between 10-30% Treated With Hypomethylating Agents Versus Intensive Chemotherapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2788-2788 ◽  
Author(s):  
Aziz Nazha ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Courtney D. DiNardo ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Regression Model ◽  
Conflicts Of Interest ◽  
World Health ◽  
Refractory Anemia ◽  
Intensive Chemotherapy ◽  
Hypomethylating Agents ◽  
Specific Protocol ◽  
Bone Marrow Blasts

Abstract Background In 2001, the World Health Organization modified the French-American-British (FAB) classification for myelodysplastic syndrome (MDS) by folding the refractory anemia with excess blasts in transformation (RAEB-t) category into acute myeloid leukemia (AML). Whether this group of patients (pts) should be treated with AML versus MDS therapy remains controversial. A subset analysis of the AZA-001 trial showed that azacitidine prolongs overall survival (OS) in elderly pts with low blasts AML (bone marrow blasts [BM] 20-30%). Aim To compare the clinical outcome and OS of patients with MDS or AML with BM blasts between 10-30%, treated with hypomethylating agents (HMA) vs intensive chemotherapy (IC). Patients and Methods We conducted a retrospective analysis of newly diagnosed pts with MDS (or AML by WHO) and BM blasts between 10-30% treated with either HMA (alone or in combination with investigational therapies) or IC on clinical trials. Eligibility was based on pt characteristics and specific protocol inclusion criteria. A univariate Cox proportional hazards regression model was used to evaluate the overall effects of treatments and outcome (remission duration (RD), and OS). Then a regression model with the interactions between treatments and baseline covariates were used for subgroup analysis. The final model was obtained by a stepwise selection using 0.05 as a cut off of significant values. Results 330 patients were included in the final analysis, with 93 (28%) HMA-treated pts and 237 (72%) pts treated with IC. Clinical characteristics at diagnosis are summarized in Table1. The overall response rate (ORR= CR+CR p) was 42% for the pts who treated with HMA and 60% for pts treated with IC (P = 0.01). The median RD was similar between the two groups (14.7 mos (m) vs. 14.7 mos, respectively, P = 0.74). Early induction mortality was also similar among the two groups (4-week mortality was 5% vs. 7%, respectively, and the 8-week mortality was 10% vs. 13 %, respectively). With median follow up of 37 mos (range, 1-94 mos), the median OS was 18.8 mos for pts who treated with HMA vs. 14.6 mos for pts treated with IC (P = 0.32). Moreover, the BM blasts percentage did not impact the overall outcome. In multivariate analysis, treatment with IC was associated with worse OS compared to HMA (HR 2.09, 95% CI 2.07-3.17, P = 0.003) but not for RD (HR 0.43, 95% CI 0.89-2.68, P = 0.13). Conclusion Although patients with MDS or AML with BM blasts between 10-30% initially achieve a higher ORR when treated with IC compared to HMA-based therapy, the OS was better for pts treated with HMA after accounting for all other covariates. Interestingly, BM blast percentages within this cohort did not impact overall outcome suggesting that pts with BM blasts 20-30% may achieve better outcome with MDS therapy. Disclosures: No relevant conflicts of interest to declare.

Monosomal Karyotype In Myelodysplastic Syndromes, with or without Monosomy 7 or 5, Is Prognostically Worse Than An Otherwise Complex Karyotype

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2918-2918
Author(s):  
Mrinal M. Patnaik ◽  
Curtis A. Hanson ◽  
Janice Hodnefield ◽  
Ryan Knudson ◽  
Van Dyke L Daniel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clin Oncol ◽  
Myelodysplastic Syndromes ◽  
World Health ◽  
Complex Karyotype ◽  
Bone Marrow Blast ◽  
Monosomy 7 ◽  
Free Survival ◽  
Autosomal Chromosome ◽  
Monosomal Karyotype

Abstract Abstract 2918 Background: Monosomal karyotype (MK) is defined as the presence of two or more distinct autosomal chromosome monosomies or a single autosomal monosomy associated with at least one structural abnormality (Breems DA et al. J Clin Oncol 2008; 26: 4791). In acute myeloid leukemia (AML), MK has been associated with a worse prognosis than otherwise complex karyotype, regardless of the specific type of autosomal chromosome involved (Breems DA et al. J Clin Oncol 2008; 26: 4791). Whether or not these observations also hold true for myelodysplastic syndromes (MDS) is currently unknown. Objective: To determine if MDS with complex karyotype can be prognostically sub-stratified further based on the presence or absence of MK and if prognosis in MDS with MK is in addition affected by the presence or absence of monosomy 7 or monosomy 5. Methods: The Mayo Clinic database for MDS was used to identify consecutive patients with complex karyotype, defined as the presence of three or more numerical or structural cytogenetic abnormalities. World Health Organization (WHO) criteria were used for MDS diagnosis and leukemic transformation (Vardiman JW et al. Blood 2009; 114: 937). Overall and leukemia-free survivals were calculated from the time of initial cytogenetic studies documenting complex karyotype. Results: A total of 127 MDS patients (median age 70 years; 79 males) with complex karyotype were identified. Amongst them, 106 (83%) met the above-stipulated criteria for MK and 21 (17%) had complex karyotype without monosomies. The MK in the 106 patients included monosomy 7 and/or monosomy 5 in 73 cases. The three complex karyotype subsets (i.e. complex without monosomies vs. MK that included monosomy 7 and/or 5 vs. MK excluding monosomy 7 or 5) were not significantly different in terms of age and sex distribution, hemoglobin level, leukocyte or platelet count, bone marrow blast percentage or International Prognostic Scoring System (IPSS) risk score. However, survival was significantly inferior in patients with MK compared to those with complex karyotype without monosomies (p=0.01; HR 1.9, 95% CI 1.1–3.3). Multivariable analysis identified MK (p=0.002), advanced age (p=0.0004), increased bone marrow blast percentage (0.04), but not IPSS risk category (p=0.34), as independent risk factors for survival. Interestingly, there was no difference in survival among MK patients further sub-stratified by the presence or absence of monosomy 7 and/or monosomy 5 (Figure 1). Although not statistically significant, leukemia-free survival was also worse in patients with MK compared to those with complex karyotype (p=0.11; HR 2.7, 95% CI 0.8–9.0); none of the aforementioned variables significantly affected leukemia-free survival. Conclusions: Monosomal karyotype in MDS identifies a prognostically worse subgroup of patients with complex karyotype. Furthermore, in the context of MK, autosomal monosomies other than monosomy 7 or monosomy 5 are prognostically as detrimental. Disclosures: No relevant conflicts of interest to declare.

CNS involvement in small noncleaved-cell lymphoma: is CNS disease per se a poor prognostic sign?

1991 ◽  
Vol 9 (11) ◽  
pp. 1973-1982 ◽  
Author(s):  
T B Haddy ◽  
M A Adde ◽  
I T Magrath
Keyword(s):  
Bone Marrow ◽  
Cell Lymphoma ◽  
Bone Marrow Involvement ◽  
Serum Lactate Dehydrogenase ◽  
Event Free Survival ◽  
Cns Involvement ◽  
Extensive Disease ◽  
Free Survival ◽  
Cns Disease ◽  
Cns Relapse

Of 120 patients with small noncleaved-cell lymphoma who were entered sequentially on four National Cancer Institute (NCI) protocols, 29 (24%) had CNS involvement at some time in their clinical course. Seventeen had initial CNS involvement, and 12 developed CNS involvement at the time of first relapse. All 29 patients had extensive disease at presentation. The median serum lactate dehydrogenase (LDH) levels at presentation were 1,150 IU/L for patients with initial CNS involvement and 1,083 IU/L for patients with CNS involvement at relapse. CNS disease was significantly associated with serum LDH levels (P less than .0001), bone marrow involvement (P less than .0001), and jaw involvement (P = .018), but not involvement of the abdomen. There were nine long-term survivors among the 29 patients (31%). CNS disease did not appear to confer a worse prognosis on these patients than on patients without CNS involvement who had similar degrees of serum LDH elevation or who had bone marrow involvement, suggesting that extensive disease rather than CNS involvement was responsible for the poor prognosis. Event-free survival for patients with serum LDH levels above 500 IU/L was not different whether CNS disease was present or not (P = .29), nor was event-free survival different for patients with stage IV disease, whether CNS disease was present or not (P = .92). Although some patients had CNS radiation, there was no evidence that this was of therapeutic benefit. Intrathecal (IT) chemoprophylaxis effectively prevented spread to the CNS in patients without initial CNS involvement. Five of 18 patients (28%) who received no IT prophylaxis had CNS relapse (four isolated to the CNS), but only seven of the 85 patients (8%) who received IT prophylaxis had CNS relapse (two isolated to the CNS). The differences in overall and isolated CNS relapse rates were statistically significant (P = .034 and P = .008, respectively).

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