Prognostic Interactions Between SRSF2, ASXL1, and IDH Mutations in Primary Myelofibrosis and Determination of Added Value to Cytogenetic Risk Stratification and DIPSS-Plus

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 430-430
Author(s):  
Terra L. Lasho ◽  
Naseema Gangat ◽  
Christy Finke ◽  
Rebecca R. Laborde ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Stratification ◽  
Blood Cell ◽  
Lower Risk ◽  
Primary Myelofibrosis ◽  
Added Value ◽  
Prognostic Relevance ◽  
Idh Mutations ◽  
Mutational Hotspots ◽  
Risk Patients

Abstract Abstract 430 Background: The Dynamic International Prognostic Scoring System (DIPSS-plus) uses eight risk factors to predict overall survival (OS) in primary myelofibrosis (PMF): unfavorable karyotype, peripheral blood (PB) blast count ≥1%, platelet count <100 × 109/L, white blood cell count (WBC) >25 × 109/L, hemoglobin level <10 g/dL, red blood cell transfusion need, constitutional symptoms, and age >65 years (JCO 2011;29:392). Among these risk factors, karyotype holds a dominant role in predicting both overall (OS) and leukemia-free (LFS) survival (Blood 2011;118:4595). More recently, certain PMF-associated somatic mutations (IDH, EZH2, ASXL1, SRSF2) have been reported (in print or at recent meetings) to carry prognostic relevance for OS or LFS in PMF while other mutations (JAK2, MPL, TET2, SF3B1) did not. The purpose of the current study was to examine the individual and combined prognostic relevance of the former in the context of cytogenetic risk stratification and DIPSS-plus. Methods: An updated Mayo Clinic database of 1008 karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify study patients in whom DNA at time of referral was available for mutation analysis. OS and LFS were calculated from the time of referral, which was also the time of study sample collection. Results: In an ongoing project, a total of 397 PMF patients have so far been studied for IDH1/2 (n=367), SRSF2 (n=355), ASXL1 (n=260) and EZH2 (n=43) mutations. The corresponding mutational frequencies were 5.4% (20/367), 14.4% (51/355), 31.2% (81/260) and 7% (3/43). These mutations were not exclusive of either each other or JAK2 or MPL mutations and a significant clustering was noted between SRSF2 and IDH mutations; IDH mutational frequency was 21% (10/48) in SRSF2-mutated versus 3% (9/279) in unmutated cases (P<0.0001). Mutational hotspots were P95 in exon 1 for SRSF2 and exons 1, 2 and 5 for ASXL1. OS and LFS effect have so far been examined for ASXL1, SRSF2 and IDH 1/2 mutations; in univariate analysis, all three mutations significantly affected OS (ASXL1 RR 1.9, 95% CI 1.4–2.7; SRSF2 RR 1.7, 95% CI 1.2–2.5; IDH 1/2 RR 1.8, 95% CI 1.1–3.1) whereas only IDH 1/2 (RR 5.5, 95% CI 2.5–11.8) and SRSF2 (RR 3.5, 95% CI 1.7–7.0) but not ASXL1 (p=0.29) mutations affected LFS. The observed prognostic relevance for OS was sustained during multivariable analysis that included ASXL1 with either SRSF2 or IDH mutations, as co-variates, whereas both IDH and SRSF2 mutations remained significant for LFS. Based on the above observations, study patients were classified into two groups: i) unmutated for ASXL1, SRSF2 and IDH1/2 (all unmutated; n=146) and ii) mutated for at least one of the three mutations (one or more mutated; n=130); the latter group constituted 62%, 52%, 18% and 27% of DIPSS-plus high, intermediate-2, intermediate-1and low risk patients, respectively (p<0.0001). The corresponding rates for patients with favorable and unfavorable karyotype were 47% and 43% (p=0.7) and for normal vs. abnormal karyotype were 53% and 36% (p=0.008). The “all unmutated group”, compared to the “one or more mutated group” enjoyed a significantly superior OS (RR 0.5, 95% CI 0.4–0.7) and LFS (RR 0.3, 95% CI 0.2–0.7) that was DIPSS-plus-independent for OS (p=0.03) and karyotype-independent for LFS (p=0.004). The prognostic value of distinguishing “all unmutated” from “one or more mutated” patient groups was most evident for DIPSS-plus intermediate-2 or lower risk groups (p=0.002) and its added value for high-risk group was limited (p=0.23) (Figure). Conclusions: A concomitant analysis strategy reveals that SRSF2, ASXL1 and IDH mutations carry inter-independent prognostic relevance for overall or leukemia-free survival in PMF. Any one of these three mutations is more likely to occur in patients with normal karyotype and such an event predicts shortened survival that is not accounted for by DIPSS-plus and a higher risk of leukemic transformation that is independent of karyotype. The current study suggests that such information might be useful in treatment decisions involving intermediate-2 or lower risk patients. Disclosures: No relevant conflicts of interest to declare.

Predictors of Greater Than 80% Two-Year Mortality in Primary Myelofibrosis: A Mayo Clinic Study of 884 Karyotypically-Annotated Cases

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2806-2806
Author(s):  
Ayalew Tefferi ◽  
Naseema Gangat ◽  
Rakhee Vaidya ◽  
Kebede Begna ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Blood Cell ◽  
Mayo Clinic ◽  
Roc Analysis ◽  
Primary Myelofibrosis ◽  
Mortality Rates ◽  
Allogenic Stem Cell Transplantation ◽  
High Risk Disease ◽  
Blast Count

Abstract Abstract 2806 Background: A high degree of prognostic certainty is required to recommend or discourage high risk treatment procedures in primary myelofibrosis (PMF). The Dynamic International Prognostic Scoring System (DIPSS-plus) uses eight risk factors to predict overall survival (OS) in PMF: unfavorable karyotype, peripheral blood (PB) blast count ≥1%, platelet count <100 × 109/L, white blood cell count (WBC) >25 × 109/L, hemoglobin level <10 g/dL, red blood cell transfusion need, constitutional symptoms, and age >65 years (Gangat et al. JCO 2011;29 :392). The presence of four or more of these risk factors defines high-risk disease. purpose: The purpose of the current study was to enhance the prognostic weight of some of the DIPSS-plus risk factors with the intent to identify one or two parameters that can reliably predict death in the first two years of disease. Methods: An updated Mayo Clinic database of 884 karyotypically-annotated patients with PMF was used. Calculations of 2-year mortality rates and variables considered for prognostic value were from time of referral to the Mayo Clinic. Cytogenetic risk categorization per DIPSS-plus was further refined to capture additional prognostic information from monosomal karyotype (MK) (Vaidya et al. Blood 2011;117 :5612) and inv(3)/i(17q) abnormalities (Caramazza et al. Leukemia 2011;25 :82). Receiver operating characteristic (ROC) analysis was employed to define best discriminant levels. Results: To date, 564 (64%) deaths have been documented. Each one of the aforementioned DIPSS-plus risk factors was associated with a 2-year mortality rate that ranged from 42% (PB blast count ≥1%) to 60% (unfavorable karyotype). High-risk disease per DIPSS-plus was associated with 57% two-year mortality. The only risk factors that were associated with >80% two-year mortality were MK (n =19) and inv(3)/i(17q) abnormalities (n =8) and both were associated with significantly worse survival, compared to other unfavorable karyotype (n =102): HR (95% CI) of 5.1 (3.1−8.4) and 3.9 (1.7−8.8), respectively. ROC analysis identified PB blast counts of 2% and 9% (AUC 0.62) and WBC of 43 × 109/L (AUC 0.66) as best discriminant levels for predicting 2-year mortality; OS was significantly worse in the presence of PB blast >9% (HR 4.1, 95% CI 2.8–6.1) vs. 2% to 9% (HR 1.8, 95% CI 1.5–2.2) vs. <2%; the corresponding 2-year mortality rates were 73%, 46% and 25%. OS was also significantly worse in the presence of WBC ≥40 × 109/L (HR 2.8, 95% CI 2.2–3.6) vs. 26–39 × 109/L (HR 1.6, 95% CI, 1.2–2.1) vs. <26 × 109/L; the corresponding 2-year mortality rates were 63%, 42% and 28%. Two-year mortality rates exceeded 80% in the presence of any two of the following: PB blast count >9%, WBC ≥40 × 109/L or unfavorable karyotype other than MK or inv(3)/i(17q). Conclusions: A greater than 80% 2-year mortality in PMF is predicted by the presence of MK, inv(3)/i(17q) abnormalities, or any two of the following: PB blast >9%, WBC ≥40 × 109/L, other unfavorable karyotype. Such patients and those with high DIPSS-plus risk should be referred to allogenic stem cell transplantation earlier than later. Disclosures: No relevant conflicts of interest to declare.

Risk of Thromboembolic Events in ET and Early/Prefibrotic PMF: The Relevance of an Accurate Histological Diagnosis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1735-1735
Author(s):  
Serena Rupoli ◽  
Gaia Goteri ◽  
Picardi Picardi ◽  
Lucia Canafoglia ◽  
Giorgia Micucci ◽  
...  
Keyword(s):  
Risk Factors ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Vascular Events ◽  
Bone Marrow Trephine Biopsy ◽  
Increased Risk ◽  
Risk Patients ◽  
Early Primary

Abstract Abstract 1735 Background: Essential Thrombocytemia (ET) is a myeloproliferative neoplasm characterized by increased risk of vascular events. Established thrombosis risk factors are age and previous vascular events. The clinical and prognostic relevance of WHO histologic criteria for ET and prefibrotic/early Primary Myelofibrosis (PMF) has been well recognized. Our aim was to evaluate the correlation between histologic interpretation and vascular events in our series of thrombocytemias. Material and methods: From our files, we retrieved all patients consecutively diagnosed as having ET with complete clinical data (N = 283) who had undergone to a bone marrow trephine biopsy before any treatment at or within 1 year of diagnosis (N= 133). The histologic slides were reviewed in order to separate true ET cases from early/prefibrotic PMF; vaso-occlusive events at diagnosis and in the follow-up were than compared in the two groups. Results: Histologic review reclassified 61 cases as ET and 72 cases as prefibrotic/early PMF. Prefibrotic/early PMF showed a significant higher prevalence of thrombosis history and thrombotic events at diagnosis, and an increased leukocyte count than ET (22% vs 8%, 15.2% vs 1.6%, 8389/mmc vs 7500/mmc, respectively); furthermore, venous thromboses (mainly atypical) were relatively common in PMF, as opposed to WHO-defined ET. During follow-up, patients with prefibrotic PMF, although younger, showed a significant higher risk of developing thrombosis: the 15-year risk of thrombosis was 48% in prefibrotic PMF (grade 0), 16% in early PMF (grade 1, 2) and 17% in ET. Multivariate analysis confirmed that age and histopathology are independent risk factors for thrombosis during follow-up. Patients older than 60 or with prefibrotic PMF are high risk patients whereas those younger and with non prefibrotic PMF or ET should be considered at low risk (20-year risk of thrombosis 47% vs 4%, p=0.005). Conclusion: The results of present study indicate prefibrotic PMF as a myloproliferative neoplasm with the highest tendency to develop vascular events compared to early PMF and ET. Therefore we suggest to include histopathology interpretation in the risk stratification of so-called ET patients. Disclosures: No relevant conflicts of interest to declare.

Bilateral Pulmonary Artery Banding before Norwood Procedure: Survival of High-Risk Patients

2019 ◽  
Vol 68 (01) ◽  
pp. 030-037 ◽  
Author(s):  
Antonia Schulz ◽  
Nicodème Sinzobahamvya ◽  
Mi-Young Cho ◽  
Wolfgang Böttcher ◽  
Oliver Miera ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Pulmonary Artery ◽  
Lower Risk ◽  
Pulmonary Artery Banding ◽  
Norwood Procedure ◽  
High Risk Patients ◽  
Significant Difference ◽  
Bilateral Pulmonary Artery Banding ◽  
Risk Patients

Background This study reports midterm results of high-risk patients with hypoplastic left ventricle treated with initial bilateral pulmonary artery banding (PAB) before secondary Norwood procedure (NP). Methods Retrospective study of 17 patients admitted between July 2012 and February 2017 who underwent this treatment strategy because diagnosis or clinical status was associated with high risk for NP. Survival was compared with that of patients who underwent primary NP. Results Mean Aristotle comprehensive complexity score for NP would have been 19.7 ± 2.6. Risk factors included obstructed pulmonary venous return (n = 9), body weight < 2.5 kg (n = 7), total anomalous pulmonary venous connection (n = 3), and necrotizing enterocolitis (n = 1). Ten patients had a score ≥ 19.5. Early survival after PAB was 82.4% (14/17). NP was performed in 14 patients after improvement of clinical condition at a median age of 56 days and a weight ≥2,500 g. There was no 30-day mortality, but one interstage death. One patient died later after Glenn operation. One-year survival after primary PAB followed by NP was 70.6 ± 11.1%. During the same period, 35 patients with overall lower risk factors underwent primary NP; early postoperative survival and 1-year survival were 88.6 ± 5.4% and 68.6 ± 7.8%, respectively. There was no significant difference in survival between the two groups (p = 0.83) despite higher risk in the secondary Norwood group (p <0.0001). Conclusions PAB before NP in high-risk patients constituted salvage management. Primary PAB provided enough time for stabilization and control of most risk factors. It allowed midterm survival equivalent to the survival after primary NP in lower risk neonates.

scholarly journals Catheter Management and Risk Stratification of Patients With in Inpatient Treatment Due to Acute Epididymitis

2020 ◽  
Vol 7 ◽  
Author(s):  
Mike Wenzel ◽  
Marina Deuker ◽  
Maria N. Welte ◽  
Benedikt Hoeh ◽  
Felix Preisser ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Score ◽  
Inpatient Treatment ◽  
Low Risk ◽  
High Risk Patients ◽  
Catheter Group ◽  
Risk Patients ◽  
Acute Epididymitis

Objective: This study aims to evaluate catheter management in acute epididymitis (AE) patients requiring inpatient treatment and risk factors predicting severity of disease.Material and Methods: Patients with diagnosed AE and inpatient treatment between 2004 and 2019 at the University Hospital Frankfurt were analyzed. A risk score, rating severity of AE, including residual urine &gt; 100 ml, fever &gt; 38.0°C, C-reactive protein (CRP) &gt; 5 mg/dl, and white blood count (WBC) &gt; 10/nl was introduced.Results: Of 334 patients, 107 (32%) received a catheter (transurethral (TC): n = 53, 16%, suprapubic (SPC): n = 54, 16%). Catheter patients were older, exhibited more comorbidities, and had higher CRP and WBC compared with the non-catheter group (NC). Median length of stay (LOS) was longer in the catheter group (7 vs. 6 days, p &lt; 0.001), whereas necessity of abscess surgery and recurrent epididymitis did not differ. No differences in those parameters were recorded between TC and SPC. According to our established risk score, 147 (44%) patients exhibited 0–1 (low-risk) and 187 (56%) 2–4 risk factors (high-risk). In the high-risk group, patients received a catheter significantly more often than with low-risk (TC: 22 vs. 9%; SPC: 19 vs. 12%, both p ≤ 0.01). Catheter or high-risk patients exhibited positive urine cultures more frequently than NC or low-risk patients. LOS was comparable between high-risk patients with catheter and low-risk NC patients.Conclusion: Patients with AE who received a catheter at admission were older, multimorbid, and exhibited more severe symptoms of disease compared with the NC patients. A protective effect of catheters might be attributable to patients with adverse risk constellations or high burden of comorbidities. The introduced risk score indicates a possibility for risk stratification.

Added value of exercise test findings beyond traditional risk factors for cardiovascular risk stratification

2019 ◽  
Vol 292 ◽  
pp. 212-217 ◽  
Author(s):  
Amanda R. Bonikowske ◽  
Francisco Lopez-Jimenez ◽  
Maria Irene Barillas-Lara ◽  
Ahmad Barout ◽  
Sonia Fortin-Gamero ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Risk Stratification ◽  
Exercise Test ◽  
Added Value ◽  
Cardiovascular Risk Stratification ◽  
Traditional Risk Factors

Examining variation in interstage mortality rates across the National Pediatric Cardiology Quality Improvement Collaborative: do lower-mortality centres have lower-risk patients?

2018 ◽  
Vol 28 (8) ◽  
pp. 1031-1036 ◽  
Author(s):  
Katherine E. Bates ◽  
Sunkyung Yu ◽  
Ray Lowery ◽  
Sara K. Pasquali ◽  
David W. Brown ◽  
...  
Keyword(s):  
Risk Factors ◽  
Quality Improvement ◽  
Lower Risk ◽  
Pediatric Cardiology ◽  
Mortality Rates ◽  
Lower Mortality ◽  
Baseline Risk ◽  
Quality Improvement Collaborative ◽  
Risk Patients ◽  
Interstage Mortality

AbstractBackgroundAlthough interstage mortality for infants with hypoplastic left heart syndrome has declined within the National Pediatric Cardiology Quality Improvement Collaborative, variation across centres persists. It remains unclear whether centres with lower interstage mortality have lower-risk patients or whether differences in care may explain this variation. We examined previously established risk factors across National Pediatric Cardiology Quality Improvement Collaborative centres with lower and higher interstage mortality rates.MethodsLower-mortality centres were defined as those with >25 consecutive interstage survivors. Higher-mortality centres were defined as those with cumulative interstage mortality rates >10%, which is a collaborative historic baseline rate. Baseline risk factors and perioperative characteristics were compared.ResultsSeven lower-mortality centres were identified (n=331 patients) and had an interstage mortality rate of 2.7%, as compared with 13.3% in the four higher-mortality centres (n=173 patients, p<0.0001). Of all baseline risk factors examined, the only factor that differed between the lower- and higher-mortality centres was postnatal diagnosis (18.4 versus 31.8%, p=0.001). In multivariable analysis, there remained a significant mortality difference between the two groups of centres after adjusting for this variable: adjusted mortality rate was 2.8% in lower-mortality centres compared with 12.6% in higher-mortality centres, p=0.003. Secondary analyses identified multiple differences between groups in perioperative practices and other variables.ConclusionsVariation in interstage mortality rates between these two groups of centres does not appear to be explained by differences in baseline risk factors. Further study is necessary to evaluate variation in care practices to identify targets for improvement efforts.

Effect of the Number of Prognostically Relevant Mutated Genes on Survival and Leukemia Progression in Primary Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 104-104
Author(s):  
Paola Guglielmelli ◽  
Terra L. Lasho ◽  
Flavia Biamonte ◽  
Johannah Score ◽  
Carmela Mannarelli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Risk Stratification ◽  
Validation Cohort ◽  
Univariate Analysis ◽  
Primary Myelofibrosis ◽  
Risk Category ◽  
Prognostic Relevance ◽  
High Risk Category ◽  
Risk Categories

Abstract Background The median survival (OS) of patients with primary myelofibrosis (PMF; 6.5y) is significantly shortened compared to reference population (Cervantes et al, JCO 2012; 30:2981). OS is predicted by the four risk categories of IPSS, Dynamic-IPSS and DIPSS-plus score, nevertheless pts heterogeneity persists within these categories, necessitating improved risk stratification. We recently reported that pts harboring mutations in any one of the prognostically relevant ASXL1, EZH2, IDH1/2 and SRSF2 genes constitute a IPSS-and DIPPS-plus independent Molecular High Risk category (MHR+) characterized by significant reduction of OS and leukemia free survival (LFS) (Vannucchi et al, Leukemia 2013). The aim of this work was to analyze the impact of the number of prognostically relevant mutated genes on OS and LFS in PMF. Patients and methods Two independent cohorts are included, a “test cohort” from Europe, analyzed at diagnosis, and a “validation cohort” from Mayo Clinic, analyzed at any time after diagnosis. Mutation analysis was performed in DNA from whole blood or granulocytes using RTQ-PCR, HRM and direct sequencing; all mutations were confirmed at least twice. The prognostic value of the molecular variables with regard to OS and LFS was analyzed by Cox regression. Test cohort It included 490 pts (median age 61y; males = 301) risk stratified by IPSS into high (n=74, 15%), intermediate-2 (n=93, 19% ), intermediate-1 (n=147, 30%) and low (n=176, 36%). The median follow-up was 3.63y (95% CI, 0.06-28.33); 161 pts died (33.0%), of whom 76 (15.6%) had progressed to acute leukemia after a median of 3.4y (0.04-28.3) from diagnosis. One hundred forty-six pts (29.8%) presented at least one of the four aforementioned mutated genes and were classified as MHR+. The OS of MHR+ pts was significantly reduced compared to patients with no mutations (n=344): 80.7 vs 148.9 mo (HR 2.2, CI95% 1.6-3.03). One hundred twelve (22.8%) pts had 1 mutation and 34 (6.9%) had 2 or more mutations. In univariate analysis presence of 2 or more mutated genes was significantly more detrimental for OS (29.5mo; HR 4.12, IC95% 2.6-6.4) than having 1 mutated gene (84.2mo; HR 1.8, IC95% 1.2-2.5) compared with having no mutations (148.9mo). Multivariate analysis results adjusted for IPSS indicated that having two or more mutations was an independent prognostic factor for OS (HR 2.9, 95% CI 1.8-4.5). Notably, the prognostic relevance of harboring two or more mutations involved both lower (low and intermediate-1; HR 1.87, 95% CI 1.3-2.6) and higher (intermediate-2 and high; HR 1.6, 95% CI 1.2-2.1) categories of IPSS. Also LFS resulted significantly shorter (129mo; HR 3.1, 95%CI 1.9-4.8) in MHR+ pts compared with pts with no adverse mutations (323mo). Having 2 or more mutations correlated with greater reduction of LFS (79.6mo; HR 7.02, CI95% 3.9-12.6) than having one mutation only (133.9mo; HR 2.2, IC95% 1.3-3.7) as compared with no mutations (323.2mo). Multivariate analysis showed that IPSS high risk category (HR 4.5; 95% CI 2.3-8.8) and two or more mutated genes (HR 5.3; 95% CI 2.9-9.8) predicted independently for a significant reduction in LFS. The negative impact on LFS of having 2 or more mutated genes compared to one or no mutations was maintained in the lower (HR 6.4, 95% CI 2.6-15.2) and higher (HR 5.5, 95% CI 2.3-12.8) risk categories. Validation cohort Validation cohort included 262 patients (median age 64 years; males = 167) risk stratified by DIPSS-plus into high (n=89, 34%), intermediate-2 (n=92, 35%), intermediate-1 (n=46, 18%) and low (n=34, 13%). One hundred forty-six pts (56%) displayed none of the four aforementioned mutations, 93 (36%) harbored one mutation whereas 23 (9%) harbored two or more mutations. In univariate analysis, having two or more mutations (HR 3.7; 95% CI 2.2-6.1) was significantly more detrimental for OS than having no mutations, which is more favorable than having one mutation (HR 1.9; 95% CI 1.4-2.7). When adjusted for DIPSS-plus, the presence of two or more mutations retained its significance (HR 2.1; 95% CI 1.3-3.6) and outperformed ASXL1 mutation alone in its prognostic relevance Conclusions Overall, these results show that the number of prognostically relevant mutated genes correlate with OS and LFS in pts with PMF, suggesting that screening for these mutations might help to improve risk stratification. Disclosures: No relevant conflicts of interest to declare.

Risk stratification including FOXO1 fusion status (FOXO1) in patients with rhabdomyosarcoma (RMS) treated on six recent frontline trials: A report from the Children's Oncology Group (COG).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10528-10528 ◽  
Author(s):  
Emily Hibbitts ◽  
Douglas S. Hawkins ◽  
Carola A. S. Arndt ◽  
Yueh-Yun Chi
Keyword(s):  
Risk Factors ◽  
Clinical Trials ◽  
Risk Stratification ◽  
Goodness Of Fit ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Prognostic Impact ◽  
Survival Trees ◽  
Risk Patients ◽  
Metastatic Sites

10528 Background: Clinical risk factors associated with outcome in children with either localized or metastatic RMS were identified by Meza et al. (2006) and Oberlin et al. (2008). We re-examined risk stratification by adding FOXO1 to traditional clinical prognostic factors in children with localized or metastatic RMS in a large cohort from COG frontline clinical trials. Methods: Data from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1,853 eligible patients (two studies each for low, intermediate and high risk patients). Survival tree regression for event-free survival (EFS) and overall survival (OS) was conducted to determine prognostic impact of risk factors. Recursively, the factor most strongly associated with outcome was selected for branching and split using a goodness of fit measure. Factors included were age, FOXO1, group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Results: 5-year overall EFS and OS was 0.67 (SE, 0.01) and 0.77 (SE, 0.01), respectively. Survival trees for EFS and OS found localized versus metastatic at the first split and included FOXO1 as a significant risk factor. Conclusions: FOXO1 improves risk stratification of patients with localized RMS, although histology and pattern of metastases are more predictive for patients with metastatic RMS. Our findings support incorporation of FOXO1 in risk stratified clinical trials. [Table: see text]

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation in Myelodysplastic Syndrome (MDS) Patients at Lower Risk According to International Prognostic Scoring System (IPSS) : A Retrospective Study on Behalf of the Cmwp of the EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2530-2530
Author(s):  
Marie Robin ◽  
Porcher Raphael ◽  
Anja van Biezen ◽  
Liisa Volin ◽  
Ghulam J. Mufti ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cells ◽  
Bone Marrow ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Lower Risk ◽  
Conditioning Regimen ◽  
Refractory Anemia ◽  
Hematopoietic Stem ◽  
Risk Patients

Abstract The allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment in patients with MDS. Indeed, many retrospective studies have shown that the higher risk patients according to IPSS (intermediate-2 and high) have a better overall survival with HSCT if performed at time of diagnosis while HSCT in lower risk patients (low and intermediate-1) should be postponed. Actually, some lower risk patients have poor prognostic features leading to propose the transplantation before they evolve to a higher risk. In this registry study from the CMWP, we analyzed outcome of patients who were diagnosed “low risk MDS” and who finally were transplanted without evolving to a higher risk. As more and more of these patients are proposed to the transplantation, their survey may give information about their prognostic risks. All adult patients transplanted between 2000 and 2011 and registered in the EBMT registry could be included if they have a “low risk” MDS at time of diagnosis and at time of transplantation. Overall and progression-free survival (OS and PFS) were estimated using Kaplan-Meier product limit estimator. For competing risk, cumulative incidence functions were estimated using usual methodology. Cox proportional hazard model were used to test the potential risk factors (age, gender, CMV recipient/donor, disease, IPSS, transfusion, donor type, conditioning). Missing data were handled through multiple imputations by chained equations methods. 291 patients met the inclusion criteria: 126 women and 165 men. Median age at diagnosis was 53 years and inter-quartile range (IQR) from 44 to 59. The majority of patients have refractory anemia or refractory cytopenia with multilineage dysplasia (66%), while one third of patients have refractory anemia with excess blasts. Most patients were intermediate-1 (80%) and required transfusions before the transplantation (84%). Median age at time of transplantation was 55 years (IQR: 46-60). Median time from diagnosis to transplantation was 11 months (IQR: 7-22). Donor was an HLA matched sibling in 122 (42%) patients and an unrelated donor in the remaining patients. The preferred source of stem cells was peripheral blood stem cells (PB) (78%) followed by bone marrow (19%) and cord blood (3%). Conditioning regimen consisted in a reduced intensity conditioning regimen in the majority of patients (59%) and 58% received an in vivo T depletion. PFS and OS of the whole patients are shown in Figure 1 A and 1 B. Cumulative incidence of grade II-IV acute GVHD, chronic GVHD, non-relapse mortality and relapse are shown in Figure 2 A-D. Multivariate analysis with original data set (excluding missing data) found the following factors as poor prognostic for PFS: age < 35 years (Hazard ratio (HR): 4.22, p=0.009) or > 45 years (p<0.05), blast count in bone marrow > 5% (HR: 1.67, p=0.05), bone marrow (HR: 2.18, p=0.003) or cord blood (HR: 5.28, p=0.014) as sources of stem cells rather than PB and CMV serostatus positive for the recipient and negative for the donor (HR: 2.50, p=0.002) while transfusion before the transplantation (HR): 0.51, p=0.013) and T-depletion (HR: 0.60, p=0.43) were protective. The second multivariate analysis included all patients with imputed datasets showing similar results. To conclude, outcome after HSCT in patients with lower risk IPSS are better than those observed in higher risk. In favorable transplant condition (PB, T-depletion), expected OS reaches 70% with a low mortality rate after the second year which could be a valid option in some lower risk patients presenting some “high risk factors” as poor molecular biology or resistance to agents stimulating erythropoiesis. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Blaise: Sanofi: Honoraria, Research Funding.

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