Associations and Prognostic Interactions Between Circulating Levels of Hepcidin, Ferritin, and Inflammatory Cytokines in Primary Myelofibrosis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2831-2831
Author(s):  
Animesh Pardanani ◽  
Biruk Mengistu ◽  
Christy Finke ◽  
Terra L Lasho ◽  
Ayalew Tefferi
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Red Cell ◽  
Ineffective Erythropoiesis ◽  
Cytokine Levels ◽  
Circulating Levels

Abstract Abstract 2831 Background and Aims: Primary myelofibrosis (PMF) is characterized by ineffective erythropoiesis, an underlying inflammatory state and potentially, iron overload in the setting of red cell transfusions. The potential interaction between these clinical variables and assessment of their independent prognostic contribution, if any, is of interest within the context of well established prognostic parameters including the DIPSS-plus model and increased circulating levels of inflammatory cytokines (J Clin Oncol. 2011 Apr 1;29(10):1356–63). Consequently, we studied the relationship between circulating levels of hepcidin (a surrogate for inflammation, iron stores and ineffective erythropoiesis), ferritin (iron stores and inflammation), red cell transfusion need (ineffective erythropoiesis) and soluble inflammatory cytokine levels in PMF patients. Methods: The diagnosis of PMF was according to WHO criteria. Inclusion in this study required availability of archived plasma, bone marrow biopsy, and cytogenetic information at the time of first referral. Plasma total hepcidin levels were measured by ELISA (USCN Life Sciences, Wuhan, China). Serum ferritin was measured as part of routine clinical assessment (normal range: males: 24–336 mcg/L; females: 11–307 mcg/L). Concentrations of plasma cytokines were analyzed in duplicate by using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results: Two hundred and three PMF patients met the above stipulated criteria; 136 (67%) were males and the median age at referral was 63 years (range 17–83). Their dynamic international prognostic scoring system (DIPSS)-plus risk categorization was: low-risk 22 (11%), intermediate-1 26 (13%), intermediate-2 85 (42%) and high-risk 70 (34%). Hepcidin levels (median 156279 pg/mL; range 8082–2088002) were strongly correlated with serum ferritin (n=146; median 207 mcg/L; range 14–5367) (r2=0.43, p <0.0001). Both were directly correlated with red cell transfusion need and age, and inversely with hemoglobin level (all p <0.05); however, there was no correlation with increased levels of inflammatory cytokines (>3 standard deviation above mean of normal controls for IL-2 and/ or IL-8) (p>0.05). At a median follow up of 35 months, 104 (51%) deaths and 18 (9%) leukemic transformations were recorded. In univariate analysis, increased levels of hepcidin (HR=2.0; p=0.0006) and ferritin (HR=2.7; p<0.0001) were predictive of inferior overall survival and this significance was sustained during multivariable analysis that included either increased inflammatory cytokine levels (HR=3.2 and 2.7, respectively) or transfusion need (HR=1.7 and 2.2, respectively) as covariates. When all 4 variables (i.e. increased levels of hepcidin, ferritin, inflammatory cytokines and transfusion need) were considered together in the Cox model, only increased inflammatory cytokine levels retained their prognostic significance (HR=2.7; p=0.0046). Furthermore, neither increased ferritin nor increased hepcidin levels were prognostically significant for overall survival when tested either individually or together against the DIPSS-plus model (p>0.05). In univariate analysis, increased hepcidin level, but not increased ferritin or transfusion need, was predictive for inferior leukemia-free survival (HR=2.8; p=0.04) and this significance was sustained in multivariable analysis that included either cytogenetic risk categories (very-high risk versus high-risk versus other) (HR=2.7; p=0.046) or thrombocytopenia (platelet count <100 × 109/L) (HR=2.7; p=0.047) as covariates. Conclusions: Circulating levels of hepcidin and ferritin are highly correlated variables in PMF and appear to provide redundant prognostic information for overall survival in this setting. The lack of correlation with inflammatory cytokines suggests that ineffective erythropoiesis may be the common link for their apparent prognostic value noted during univariate analysis. In contrast to inflammatory cytokines, neither hepcidin or ferritin levels were useful as a complement to the DIPSS-plus prognostic model in the current analysis. The relationship between hepcidin and leukemia-free survival is intriguing however the pathogenetic mechanism remains obscure and needs confirmation in additional patients. Disclosures: No relevant conflicts of interest to declare.

Macrophage Depletion Leads to Modification of Thalassemic Phenotype.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2023-2023 ◽  
Author(s):  
Pedro Ramos ◽  
Ella Guy ◽  
Nan Chen ◽  
Robert W. Grady ◽  
Barry S. Coller ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Inflammatory Cytokines ◽  
Red Cells ◽  
Beta Thalassemia ◽  
Red Cell ◽  
Ineffective Erythropoiesis ◽  
Protective Function ◽  
Large Expansion

Abstract Abstract 2023 Poster Board I-1045 Macrophages represent an important link between erythropoiesis and iron metabolism. They support maturation and differentiation of erythroblasts and clear senescent red cells from circulation, thus recycling iron within the hematopoietic system. However, little is known about the role of macrophages in conditions of ineffective erythropoiesis like beta-thalassemia intermedia (β-TI) or sickle cell anemia (SCD). Our goal was to study the role of macrophages under such conditions, where there is a large expansion of the erythron, the lifespan of the red cells is decreased, and both iron absorption and organ iron content are increased. Clodronate liposomes have been shown to efficiently eliminate macrophages from spleen, liver and bone marrow when administered by intravenous injection. Therefore, we utilized this technique to eliminate macrophages from the spleen, liver and bone marrow of β-TI and SCD mice. Three different treatment schedules were used; a) acute high dose; b) medium term split dose; c) chronic low dose. Animals were analyzed for erythropoietic and pathological parameters. All treatments effectively depleted splenic and bone marrow macrophages as shown by flow citometric and immunohistochemical analyses. At doses that led to only a small decrease of hemoglobin (Hb) levels in normal mice, clodronate treatment induced high level of mortality in β-TI and SCD mice (70% and 75%, respectively). In contrast, administration of clodronate to mice affected by beta-thalassemia major, mice that do not make any adult or fetal Hb/mature red cells, caused no mortality suggesting that circulating abnormal red cells might be responsible for the mortality observed in β-TI and SCD mice. Pathological analysis of β-TI mice revealed the formation of thrombi in the lungs and heart to be the likely cause of death. Analysis of SCD mice is in progress. β-TI and SCD have been described as hypercoagulable states with a high risk of thrombosis. Damaged red cell membranes and ROS have been implicated as factors that increase the risk of thrombosis in β-TI and SCD patients. We hypothesize that clodronate treatment enhances this process. To test this hypothesis, we administered an anti-coagulant (heparin) and an anti-oxidant (NAC) to β-TI mice. Both these treatments resulted in increased survival from 31% to 65% compared to clodronate alone. Analysis of SCD animals is in progress. β-TI mice that survived clodronate treatment exhibited a milder thalassemic phenotype, characterized by increased Hb (∼1.5g/dL), HCT (∼7%) and RBC count (∼2e6 cells/ul), partially associated with a decreased RBC clearance. Ineffective erythropoiesis and splenomegaly were also ameliorated (∼40% decrease in spleen size). Animals depleted of macrophages also showed a marked decrease in serum iron parameters, but no difference in their organ iron concentrations. Analysis of hepcidin expression is in progress. To further corroborate these observations, β-TI mice are being crossed with mice expressing the human diphtheria toxin (CD11b-DTR) which allows for conditional depletion of macrophages. Our data suggests that macrophages play a major role in conditions of abnormal red cell production and ineffective erythropoiesis. In the former case, they have an important protective function related to the high risk of thrombosis associated with β-TI and SCD. In the latter, macrophages may act as negative modulators of erythropoietic development. The amelioration of splenomegaly and ineffective erythropoiesis observed suggests that erythroid cells might proliferate less and/or differentiate more in the absence of macrophages. One hypothesis is that macrophages sense erythroid maturation and/or differentiation and act as modulators of these processes to ensure the release of high quality red cells into the circulation. Second, macrophages, under conditions of iron overload, might produce inflammatory cytokines that further impair erythropoiesis in thalassemia. Analysis of RNA extracted from macrophages and of inflammatory cytokines in β-TI mice before and after clodronate treatment is in progress. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Identifying Novel Cell Glycolysis-Related Gene Signature Predictive of Overall Survival in Gastric Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xin Zhao ◽  
Jiaxuan Zou ◽  
Ziwei Wang ◽  
Ge Li ◽  
Yi Lei
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
High Risk ◽  
Risk Score ◽  
Malignant Tumors ◽  
Single Gene ◽  
Univariate Analysis ◽  
The Cancer Genome Atlas ◽  
Clinical Value ◽  
Specificity And Sensitivity

Background. Gastric cancer (GC) is believed to be one of the most common digestive tract malignant tumors. The prognosis of GC remains poor due to its high malignancy, high incidence of metastasis and relapse, and lack of effective treatment. The constant progress in bioinformatics and molecular biology techniques has given rise to the discovery of biomarkers with clinical value to predict the GC patients’ prognosis. However, the use of a single gene biomarker can hardly achieve the satisfactory specificity and sensitivity. Therefore, it is urgent to identify novel genetic markers to forecast the prognosis of patients with GC. Materials and Methods. In our research, data mining was applied to perform expression profile analysis of mRNAs in the 443 GC patients from The Cancer Genome Atlas (TCGA) cohort. Genes associated with the overall survival (OS) of GC were identified using univariate analysis. The prognostic predictive value of the risk factors was determined using the Kaplan-Meier survival analysis and multivariate analysis. The risk scoring system was built in TCGA dataset and validated in an independent Gene Expression Omnibus (GEO) dataset comprising 300 GC patients. Based on the median of the risk score, GC patients were grouped into high-risk and low-risk groups. Results. We identified four genes (GMPPA, GPC3, NUP50, and VCAN) that were significantly correlated with GC patients’ OS. The high-risk group showed poor prognosis, indicating that the risk score was an effective predictor for the prognosis of GC patients. Conclusion. The signature consisting of four glycolysis-related genes could be used to forecast the GC patients’ prognosis.

95 N-Acetyl cysteine as a potential treatment for equine persistent breeding-induced endometritis

2019 ◽  
Vol 31 (1) ◽  
pp. 173
Author(s):  
M. Caissie ◽  
T. Chenier ◽  
C. Gartley ◽  
E. Scholtz ◽  
R. Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Clinical Trial ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Clinical Signs ◽  
Time Points ◽  
Cytokine Levels ◽  
Uterine Inflammation ◽  
Endometrial Cytology

Persistent breeding-induced endometritis (PBIE) is a major cause of infertility in mares. Transient uterine inflammation is a normal response to breeding; however, PBIE-susceptible mares do not clear this inflammation in a timely fashion. Uterine inflammation at the time of embryonic descent from the oviducts ultimately results in early embryonic death and is seen clinically as infertility. Several risk factors for PBIE have been identified and include age, parity, anatomical conformation, such as poor perineal conformation and cervical fibrosis, as well as other reproductive tract abnormalities. N-Acetyl cysteine (NAC), a mucolytic used to treat endometritis in mares, has anti-inflammatory properties, affects inflammatory cytokines, and is a mild inhibitor of nitric oxide synthase. Increased nitric oxide, causing smooth muscle relaxation and alterations in inflammatory cytokines, has been documented in PBIE mares. The objective of our study was to determine if NAC treatment would lower nitric oxide and inflammatory cytokine levels, thereby resolving PBIE. A randomised, blinded, crossover design clinical trial was performed utilising PBIE-susceptible mares (n=10). Mares were screened for bacterial endometritis before enrolment in the study and only mares that had negative bacterial cultures were used. No other treatments were given to mares while they were enrolled in the study. Intrauterine infusion of 180mL of 3.3% NAC was performed 12h before insemination, when a follicle &gt;35mm was present. Mares were sampled for endometrial cytology and endometrial fluid to determine inflammatory cytokine (ELISA) and nitric oxide (colourimetric assay) levels at 12 and 72h post-insemination. Endometrial biopsies were taken at the same time points post-insemination to determine gene expression of inflammatory cytokines by qPCR. Clinical signs of endometrial oedema and intrauterine fluid volumes were assessed at 12 and then every 24h post-breeding. Statistical assessment of the data was performed using a repeated-measures ANOVA. Uterine inflammation, as determined by percent number of neutrophils on endometrial cytology (P=0.0006), and interleukin 6 gene expression (P=0.003) were highest at 12h. Uterine oedema was greatest at 12 and 24h (P=0.02) and uterine fluid volumes were highest at 24h (P=0.02). Interestingly, interleukin-6 protein levels were not in accordance with gene expression, and were highest at 72h. In this clinical trial, pre-breeding intrauterine treatment with NAC did not affect nitric oxide levels, cytokine gene expression, or clinical signs of PBIE. However, the pattern of inflammation noted in this study is consistent with that described in PBIE mares. Nevertheless, the assessment of inflammatory cytokines, both at the gene and protein level at different time points post-AI, in combination with clinical signs will add to the understanding of the alterations in inflammatory cytokine levels in mares susceptible to PBIE.

scholarly journals Danazol: An Effective and Underutilised Treatment Option in Diamond-Blackfan Anaemia

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Kern Y. Chai ◽  
Cara J. Quijano ◽  
Shingirai Chiruka
Keyword(s):  
Stem Cell ◽  
Targeted Therapy ◽  
Side Effects ◽  
High Risk ◽  
Red Cell ◽  
Ineffective Erythropoiesis ◽  
Viable Option ◽  
Red Cell Aplasia ◽  
Diamond Blackfan Anaemia

Diamond-Blackfan anaemia (DBA) is a rare congenital red cell aplasia that presents in infancy. The exact molecular mechanism of ineffective erythropoiesis and red cell aplasia remains unclear, rendering targeted therapy elusive. The mainstay treatment of DBA is with regular blood transfusion and long-term corticosteroids, both of which have long-term side effects. We report a case of DBA successfully treated with danazol, a synthetic androgen, and suggest that danazol be considered as a viable option in patients who become refractory to steroids and are considered high risk or unfit for allogeneic stem cell transplantation.

Prognostic Indices in Older DLBCL Patients Receiving R-CHOP: An Analysis of the U.S. Intergroup Study (E4494, CALGB 9793).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 813-813
Author(s):  
R.H. Advani ◽  
H. Chen ◽  
T.M. Habermann ◽  
V.A. Morrison ◽  
E. Weller ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Low Risk ◽  
Risk Category ◽  
Free Survival ◽  
Prognostic Tool ◽  
The Impact ◽  
The U.S

Abstract Background: We reported that addition of rituximab (R) to chemotherapy significantly improves outcome in DLBCL patients (pt) &gt;60 years (JCO24:3121–27, 2006). Although the IPI is a robust clinical prognostic tool in DLBCL, Sehn et al (ASH 2005: abstract 492) reported that a revised (R) IPI more accurately predicted outcome in pt treated with rituximab-chemotherapy. Methods: We evaluated outcomes of the Intergroup study with respect to the standard IPI, R-IPI, age-adjusted (aa) IPI for evaluable pt treated with R-CHOP alone or with maintenance rituximab. We further assessed a modified IPI (mIPI) using age ≥ 70 y as a cutoff rather than age 60 y. Results: The 267 pt in this analysis were followed for a median of 4 y. Pt characteristics were: age &gt; 70 (48%) (median=69), male 52%, stage III/IV 75%, &gt;1 EN site 30%, LDH elevated 60%, PS ≥2 15%. On univariate analysis all of these characteristics were significant for 3 y failure-free survival (FFS) and overall survival (OS). The IPI provided additional discrimination of risk compared to the R-IPI with significant differences in FFS and OS for 3 vs 4–5 factors. The aa-IPI defined relatively few pt as low or high risk. The impact of age was studied using a cut-off of 70 years in a modified IPI, yielding 4 risk groups as shown below. Conclusions: For pt ≥ 60 treated with rituximab-chemotherapy the distinction between 3 vs 4,5 factors in the IPI was significant.The IPI also provided additional discrimination of risk compared to the R-IPI. In this older group of pt, use of an age cutoff ≥70 y placed more patients in the low risk category. It is of interest to apply the mIPI in other datasets with DLBCL pt &gt;60 y. Group # Factors # Pt % 3y FFS* % 3y OS* *All risk groups significantly different; logrank p &lt; 0.001 **95 % CI: FFS (0.46,0.66), OS (0.58,0.78) ***95 % CI: FFS (0.21,0.45), OS (0.31,0.55) L: Low, LI: Low Intermediate, HI: High Intermediate, H; High IPI L 0–1 12 78 83 LI 2 28 70 80 HI 3 33 56** 68** H 4–5 37 33*** 43*** R-IPI Very Good 0 0 - - Good 1–2 40 72 81 Poor 3–5 60 46 57 aa-IPI L 0 12 78 83 LI 1 35 68 78 HI 2 44 47 59 H 3 9 31 35 mIPI (age ≥ 70) L 0–1 27 77 86 LI 2 28 62 74 HI 3 29 47 58 H 4–5 16 28 36

Erythroid Activity, Transfusion Iron Overload, and Hepcidin Levels in Patients with Myelodysplastic Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2676-2676 ◽  
Author(s):  
Luca Malcovati ◽  
Matteo G Della Porta ◽  
Coby M Laarakkers ◽  
Anna Gallì ◽  
Riccardo Albertini ◽  
...  
Keyword(s):  
High Risk ◽  
Iron Overload ◽  
Negative Impact ◽  
Multivariable Analysis ◽  
Organ Damage ◽  
Refractory Anemia ◽  
Ineffective Erythropoiesis ◽  
Ring Sideroblasts ◽  
Serum Hepcidin ◽  
Parenchymal Cells

Abstract The vast majority of patients with myelodysplastic syndrome (MDS) present with anemia, and many of them become transfusion dependent in the long term. Although transfusion iron is primarily taken up by the reticuloendothelial cells, the metal is later redistributed to parenchymal cells, and a portion of MDS patients develop parenchymal iron overload, which may have a negative impact on survival (N Engl J Med2005;352:536–8). The redistribution of transfusion iron from macrophages to parenchymal cells is likely to be modulated by hepcidin levels and erythroid activity. In fact, hepcidin prevents the release of iron from macrophages, and its synthesis is partly down-regulated by erythroid activity, which varies considerably within MDS patients. Expanded but ineffective erythropoiesis is the major mechanism responsible for anemia in low-risk MDS patients, particularly in those with refractory anemia with ringed sideroblasts, while erythroid marrow hypoproliferation is generally found in high-risk patients, typically in those with excess of blasts. We studied 76 patients with MDS followed at the Department of Hematology Oncology, University of Pavia & Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. The WHO classification criteria were employed for diagnosis of MDS. Median time since diagnosis was 12 months (range 0–241). Twenty-five patients were RBC transfusion-dependent (median number of RBC units received was 15, range 4–160). Erythroid activity was evaluated through measurement of soluble transferrin receptor (sTfR) and serum Epo, while body iron status was assessed through serum iron, TIBC and serum ferritin (sFtn). Serum hepcidin was quantified by laser desorption ionization time-of-flight mass spectrometry preceded by weak cation-exchange chromatography exploiting des-Asp hepcidin (hepcidin-24) as an internal standard (www.hepcidinanalysis.com or PLoS ONE2008;16;3:e2706). sTfR levels were found to be independently associated with hemoglobin (Hb) (the higher Hb, the lower sTfR; P&lt;.001), serum Epo (the higher Epo, the lower sTfR; P&lt;.001), and WHO category (patients with purely erythroid disorders having higher values than those with multilineage dysplasia and excess blasts; P&lt;.001), as well as with sFtn (the higher sFtn, the lower sTfR; P=.02). A wide variability in hepcidin level was found in MDS patients (median 6.98 nM, range 0.18–92.05 nM). Patients with pure erythroid disorders had significantly lower hepcidin levels compared with those with multilineage dysplasia or excess of blasts (median values 4.41, 7.62, and 15.31 nM, respectively; P&lt;.001). Transfusion-dependent patients had significantly higher hepcidin levels compared with transfusion-independent subjects (15.31 vs 4.73 nM, P&lt;.001). Significant linear correlations were found between serum hepcidin and Hb (r=−.28, P=0.02), serum Epo (r=.44, P&lt;.001), sFtn (r=.68, P&lt;.001) and sTfR (r=−.64, P&lt;.001). Considering all MDS patients, multivariable analysis showed that serum hepcidin levels were independently determined by sTfR levels (the higher sTfR, the lower serum hepcidin; P&lt;.001) and sFtn (the higher sFtn, the higher serum hepcidin; P&lt;.001). Restricting multivariable analysis to MDS patients receiving regular blood transfusion, the presence of ring sideroblasts and their number were also found to have an independent, negative impact of serum hepcidin levels (P=.005). These findings suggest that in MDS patients the redistribution of transfusion iron from reticuloendothelial cells to parenchymal cells is influenced by erythroid activity through its effect on serum hepcidin levels. MDS patients with expanded but ineffective erythropoiesis have low levels of hepcidin and enhanced iron release from macrophages, and therefore a higher likelihood of parenchymal iron loading. In particular, patients with refractory anemia with ring sideroblasts show low hepcidin levels in spite of iron overload, and therefore appear to be at high risk of parenchymal organ damage. Since these this condition has a benign clinical course, preventing organ damage through iron chelation therapy appears clinically important.

Kinase-Activating Fusions in Pediatric High-Risk B-Lineage Acute Lymphoblastic Leukemia (ALL): a Report from the Dana-Farber Cancer Institute (DFCI) ALL Consortium

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1729-1729
Author(s):  
Thai Hoa Tran ◽  
Marian H. Harris ◽  
Jonathan V. Nguyen ◽  
Traci M. Blonquist ◽  
Kristen E. Stevenson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Chromosomal Rearrangements ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Philadelphia Chromosome ◽  
B Lineage

Abstract Background. Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a diverse spectrum of chromosomal rearrangements resulting in novel chimeric fusions associated with poor prognosis when treated with conventional chemotherapy. These fusions are observed more frequently in NCI High-Risk (HR) B-ALL compared with NCI Standard Risk (SR) patients. They often activate ABL and JAK-STAT signaling pathways and have demonstrated sensitivity to the relevant tyrosine kinase inhibitors (TKIs) in in vitro assays and ex vivomodels. The objective of this study was to determine the frequency of NCI HR B-ALL patients enrolled on DFCI ALL Consortium Protocol 05-001 with a kinase-activating fusion that would be amenable to TKI therapy and to describe their associated clinical characteristics and outcomes. Methods. Between 2005-2011, 219 NCI HR, Philadelphia chromosome (Ph)-negative, B-ALL patients were enrolled on DFCI ALL Consortium Protocol 05-001, 105 of whom had sufficient material to undergo kinase fusion testing by validated multiplex reverse transcription polymerase chain reaction (RT-PCR) assays. A total of 35 kinase fusions of ABL-class (ABL1, ABL2, PDGFRB, CSF1R), JAK2 and CRLF2 rearrangements were examined. IGH@-CRLF2 and EPOR rearrangements were not assessed. Fusion products were predicted by NCBI BLAST algorithms, confirmed by singleplex PCR and Sanger sequencing and aligned using CLC Main Workbench Version 7.6.1. IKZF1 deletion (del) status had previously been assessed by multiplex ligation-dependent probe amplification (MLPA). Fisher's exact test and the Wilcoxon rank sum test were used to compare patient characteristics to those with and without any identified fusion for categorical and continuous variables respectively. Event-free survival (EFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared using a log rank test. Univariate and multivariable Cox proportional hazards models of EFS were constructed. Results. Among 105 NCI HR, Ph-negative, B-ALL patients, 16 (15%) were found to harbor an ABL-class fusion (ETV6-ABL1: n=1; FOXP1-ABL1: n=1; SFPQ-ABL1: n=1; ZC3HAV1-ABL2: n=1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n=8; PAX5-JAK2: n=4). Sixty-nine percent of patients with an identified fusion (Fusion +) had a concomitant IKZF1 del (n=11). Features associated with fusion-positivity were age of 10 years or older (p=0.003), male sex (p=0.03), Hispanic ethnicity (p=0.01) and IKZF1 del (p=0.0005) (Table 1). Fifty percent of Fusion+ patients experienced an event (induction death (n=1); induction failure (n=1); or relapse (n=6)) compared to 24% of patients without a fusion. The 5-year EFS and OS were 48% (95% CI 22-70%) and 68% (95% CI 39-85%) for Fusion+ patients compared to 78% (95% CI 67-85%) and 88% (95% CI 79-93%) for those without fusions (Figure 1). In univariate analysis, fusion-positivity (HR: 2.66, p=0.02) and IKZF1 del (HR: 3.21; p=0.0018) were each significantly associated with inferior EFS, while age and presenting leukocyte count were not. In multivariable analysis, IKZF1 del, but not fusion-positivity, retained statistical significance (HR: 2.64, p=0.02). Conclusion. Fifteen percent of NCI HR, Ph-negative, B-ALL patients enrolled on DFCI ALL Consortium 05-001 were found to have a kinase-activating fusion. Fusion+ patients frequently harbored concomitant IKZF1 deletion and had an inferior outcome. Future studies should focus on developing clinical strategies to rapidly identify these patients at diagnosis and to test whether the addition of the relevant TKIs to their treatment will improve their outcome. Disclosures Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Loh:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.

Complete Remissions (CRs) with Azacitidine Regimens Compared to Crs with 7+3 Induction Chemotherapy and the Effect on Overall Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1613-1613 ◽  
Author(s):  
Megan Othus ◽  
Mikkael A Sekeres ◽  
Sucha Nand ◽  
Guillermo Garcia-Manero ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Research Funding ◽  
Cox Regression ◽  
Intensive Therapy ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Curative Intent ◽  
Kaplan Meier ◽  
The Impact

Abstract Background: CR and CR with incomplete count recovery (CRi) are associated with prolonged overall survival (OS) for acute myeloid leukemia (AML) patients (pts) treated with curative-intent, induction therapy. For AML pts treated with azacitidine (AZA), response (CR, partial response, marrow CR, or hematologic improvement) is also associated with prolonged OS. We evaluate whether patients given AZA for myelodysplastic syndromes (MDS) or AML had longer OS if they achieved CR. We also compare the effect size of CR on OS between AZA regimens and 7+3. Patients and Methods: We analyzed four SWOG studies: S1117 (n=277) was a randomized Phase II study comparing AZA to AZA+lenalidomide or AZA+vorinostat for higher-risk MDS and CMML pts (median age 70 years, range 28-93); S0703 (n=133) treated AML pts not eligible for curative-intent therapy with AZA+mylotarg (median age 73 years, range 60-88). We analyzed the 7+3 arms of S0106 (n=301 were randomized to 7+3, median age 48 years, range 18-60) and S1203 (n=261 were randomized to 7+3, median age 48 years, range 19-60). CR was defined per 2003 International Working Group criteria. In S1117 CR was assessed every 16 weeks and patients remained on therapy until disease progression. In S0703, S0106, and S1203 CR was assessed following 1-2 induction cycles; patients not achieving CR (S0106) or CRi (S0703 and S1203) were removed from protocol treatment. OS was measured from date of study registration. To avoid survival by response bias, we performed landmark analyses of OS. We present results based on the study-specific landmark date that 75% of pts who eventually achieved a CR had done so (S1117 144 days, S0703 42 days, S0106 44 days, S1203 34 days). Pts who did not achieve CR by this date were analyzed with pts who never achieved CR. Pts who died or were lost to follow-up before this date were excluded from analyses. As a sensitivity analysis we also analyzed based on the 90% date; results were not materially different. Log-rank tests were used to compare survival curves and Cox regression models were used for multivariable modeling including baseline prognostic factors age, sex, performance status, white blood cell count, platelet count, marrow blast percentage, de novo disease (versus antecedent MDS or therapy-related disease), study arm (for S1117 only), and cytogenetic risk (IPSS criteria for S1117, SWOG criteria for S0703, S0106, and S1203). The following analysis considers morphologic CR only. S0106 treated CR with incomplete count recover (CRi) pts as treatment failures (S0703 and S1203 did not) and CRi was not defined for S1117. Hematologic improvement was only defined for S1117 patients. Results: In univariate analysis, CR was significantly associated with prolonged survival among MDS pts treated with azactidine on S1117 (HR=0.55, p=0.017), confirming the results seen in AML pts treated with azacitidine (and mylotarg, S0703, HR=0.60, p=0.054) and 7+3 (S0106 HR=0.44, p<0.001; S1203 HR=0.32, p<0.0001) (Figure 1). For each study this relationship remained significant in multivariable analysis controlling for baseline prognostic factors (S1117 HR=0.25, p<0.001; S0703 HR=0.64, p=0.049; S0106 HR=0.45, p<0.001; S1203 HR=0.41, p<0.001). There was no evidence that the impact of CR varied across the four cohorts (interaction p-value = 0.76). In the full cohort, the effect of CR was associated with a HR of 0.45 (Table 1). Conclusion: Adjusting for pt characteristics, achievement of morphologic CR was associated with a 60% improvement in OS, on average, compared to that seen in pts who don't achieve a CR, regardless of whether pts were treated with 7+3 or AZA containing regimens, and suggesting that value CR is similar of whether pts receive more or less "intensive" therapy for these high grade neoplasms. Support: NIH/NCI grants CA180888 and CA180819 Acknowledgment: The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106. Figure 1 Kaplan-Meier plots of landmark survival by response. Figure 1. Kaplan-Meier plots of landmark survival by response. Table 1 Multivariable analysis, N=878 Table 1. Multivariable analysis, N=878 Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Erba:Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Agios: Research Funding; Gylcomimetics: Other: DSMB; Juno: Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; Jannsen: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Astellas: Research Funding; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Red Cell Distribution Width (RDW) at Diagnosis of Diffuse Large B-Cell Lymphoma (DLBCL) Is Associated to Higher Mortality and Worse Overall Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5398-5398
Author(s):  
Leyre Bento ◽  
Juan Sarmentero ◽  
Ana Ortuño ◽  
Marta García-Recio ◽  
Bernardo Lopez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
High Risk ◽  
Roc Curves ◽  
Red Cell Distribution Width ◽  
Red Cell ◽  
Cell Distribution ◽  
Distribution Width ◽  
Ecog Ps

Abstract Red cell distribution width (RDW) is an indicator of the variability in the size of circulating erythrocytes (anisocytosis); different conditions can increase the RDW levels; such as hemolysis, ineffective erythropoiesis and blood transfusions. Recently, different studies have shown an association between increased levels of RDW and inflammation in different diseases, being proposed as a surrogate marker of inflammation and a strong predictor of adverse outcome. The proposed mechanism of this association departs from the finding that Inflammatory cytokines like TNFand IL-6 (part of the classic inflammatory cascade), have been found to inhibit erythropoietin-induced erythrocyte maturation, which is reflected in the RDW increase. Some reports have found a relationship between RDW and mortality related to age or several malignant or non-malignant conditions. However, there is no information about the role of RDW in overall survival (OS) of patients with DLBCL. We aim to evaluate the prognostic role of RDW levels in DLBCL patients at diagnosis. METHODS We retrospectively evaluated 83 patients with DLBCL homogenously treated in frontline with R-CHOP from 2002 to 2013 in the Son Espases University Hospital. To avoid selection bias patients were obtained from Pharmacy and Pathology Departments registries. Main clinical and prognostic factors at diagnosis were obtained from medical records. Cheson criteria were used for response assessment. The RDW was collected from the hemogram at diagnosis. The IBM SPSS STADISTICS program was used for all statistical analyses. PFS (time to progression/relapse) and overall survival (OS) (time to death) were measured from the date of ABVD onset, and were estimated according to the Kaplan-Meier method. We performed the comparisons between those interest variables with the log-rank test. A comparison between categorical variables was made with the chi-square of Fisher's exact test, as appropriate. All reported P-values were two-sided, and statistical significance was defined at P<0.05. For selecting cutoff values in RDW we used ROC curves. RESULTS: Main characteristics of patients were as follows: median age was 62 (20-86) years, 24% had ECOG PS>1, 64% advanced III-IV Ann Arbor (AA) stage, 39% B-symptoms, 51% adjusted-International Prognostic Index (a-IPI) and 39% belong to the high risk (3-5) subgroups of R-IPI Median RDW was 14.6 (11.1-21.1). Using ROC curves we selected the cutoff 14.05 for the death event. We evaluated the association of increased RDW with main prognostic factors at diagnosis. RDW >14.05 at diagnosis was associated with a more advanced age, worse ECOG PS, a more advanced AA stage, higher incidence of B symptoms and IPI>2. However, RDW was not related to disease control in terms of response to therapy (p=0.39) or relapse/progression (p=0.21) rates. Inversely, RDW>14.05 was in fact associated to a higher mortality (47%) compared to only 17% in patients with RDW≤14.05 (p=0.008). Median follow-up was 77 (20-137) months. Univariate survival analysis showed age>60 years (p=0.001), ECOG PS>1 (p=0.036), high risk R-IPI (p=0.005), a higher than 15% reduction in relative dose-intensity (RDI) (p=0.026) and RDW>14.05 (p=0.008) were significantly related to worse OS. By contrast, RDW did not significantly influence progression-free survival (p=0.19). CONCLUSIONS: Higher RDW at diagnosis in this series of DLBCL patients was related with older age, worse ECOG PS and more advanced disease but this was not translated into a worse control of disease in terms of only a small non statistically significant impact in response or PFS. By contrast higher RDW was linked to a significantly higher mortality and worse OS possibly related to a higher proinflammatory basal status and comorbidities. Patients with higher RDW may be at risk of reduction in RDI. These findings could justify including RDW in scores of comorbidities in DLBCL as well as in other malignant and non-malignant conditions. Disclosures No relevant conflicts of interest to declare.

Impact of M1a and M1b staging in patients (pts) with metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3590-3590 ◽  
Author(s):  
Hagen F. Kennecke ◽  
Jason Yu ◽  
Sharlene Gill ◽  
Winson Y. Cheung ◽  
Charles Davic Blanke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Primary Tumor ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
Primary Tumors ◽  
7Th Edition ◽  
The Impact

3590 Background: In 2009, pts with M1 colorectal cancer were divided into two subsets for the American Joint Committee on Cancer (AJCC) 7th edition. Pts with metastases (mets) confined to one organ or site at initial diagnosis became stage M1a while multiple sites or peritoneal mets became M1b. The objectives of the study are to evaluate the impact of site of mets and M1a/b staging among pts with M1 colorectal cancer. Methods: All pts referred to the BC Cancer Agency from 1999-2007 with newly diagnosed M1 colon or rectal cancer were included. Demographic, treatment, and outcome data were prospectively collected. The prognostic impact of individual sites of mets was assessed by hazard ratio estimates from univariate Cox models. Multivariable Cox proportional-hazards models were used to determine variables associated with overall survival in the entire cohort and in those undergoing resection of their primary tumor. Results: 2,049 pts with M1 disease were included. Median age was 66 years; 71% had colonic origin; 70% had their primary tumor resected; and 69% received chemotherapy. In univariate analysis, solitary mets were associated with improved survival. In multivariable analysis, M1a/b status still had significant prognostic effect. The effect remained significant in the subgroup analysis of pts with resected primary tumors when histology, T and N stage were included. Conclusions: Pts with solitary mets, including peritoneum, have superior overall survival as compared to those with multiple sites of mets. AJCC 7th edition staging that includes M1a/b provides significant prognostic information and should be considered in clinical practice and trials of pts with M1 disease who otherwise have few prognostic factors. [Table: see text]

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