Fibrinogen consumption and use of heparin are risk factors for delayed bleeding during acute promyelocytic leukemia induction

2019 ◽  
Vol 83 ◽  
pp. 106174 ◽  
Author(s):  
Bryan C. Hambley ◽  
Kelly J. Norsworthy ◽  
Jagar Jasem ◽  
Jacquelyn W. Zimmerman ◽  
Eugene Shenderov ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
Delayed Bleeding

Incidence and Risk Factors for Thrombosis in Patients with Acute Promyelocytic Leukemia. Experience of the PETHEMA LPA96 and LPA99 Protocols.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1503-1503 ◽  
Author(s):  
Pau Montesinos ◽  
Javier de la Serna ◽  
Edo Vellenga ◽  
Consuelo Rayon ◽  
Juan Bergua ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Tranexamic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Univariate Analysis ◽  
Promyelocytic Leukemia ◽  
Cerebral Stroke ◽  
Flt3 Mutations ◽  
The Impact ◽  
Ischemic Events

Abstract Background: Thrombo-ischemic events can be a severe complication in patients with active acute promyelocytic leukemia (APL). In a recently published study, the incidence of thrombosis among 90 patients with APL was 9%, and it was related to CD2 surface antigen expression, FLT3 mutations and leukocytes >10×109/L. The introduction of coagulopathy prophylaxis with tranexamic acid has not shown a benefit on hemorrhagic mortality, but its impact on the incidence of thrombotic events is unclear. Objectives:Analyze the incidence and risk factors for the development of thrombosis in patients with APL undergoing induction chemotherapy.Analyze the impact of prophylaxis with tranexamic acid on development of thrombosis. Material and methods: Between 1996 and 2005 759 patients with newly diagnosed APL were registered in the multicenter PETHEMA LPA96 and LPA99 trials. Twenty-six patients (3.5%) died due to complications before start of chemotherapy (CT). Induction consisted of ATRA plus idarubicin. In the LPA99 trial prophylactic tranexamic acid 100 mg/kg/day was introduced in case of platelets <50×109/L. At the end of the LPA99 trial its use was not recommended, and overall, initiation of tranexamic acid was reported in 257 patients (35%) We performed a univariate analysis to assess clinico-biological factors associated with thrombosis. Significant variables (p<0.05) were included in a multivariate analysis. Results: 39/759 patients (5.1%) developed thrombosis. Among 26 patients who died before initiation of CT, 6 (23%) presented with thrombotic complications: 3 cerebral stroke (CNS), 2 pulmonary embolism (PE) and 1 acute myocardial infarction (AMI). Thirty-three (4.5%) of the 733 patients in whom CT was initiated experienced thrombosis: 3 at diagnosis (1 AMI, 1 CNS and 1 deep venous thrombosis (DVT)) and 30 after the start of CT (16 DVT, 6 CNS, 3 PE, 2 AMI and 2 others). Four thrombotic events were related with initiation of tranexamic acid: 2 DVT, 1 skin necrosis and 1 renal necrosis. The following factors were related to a higher incidence of thrombosis: leukocytes >10×109/L (9% vs 4%, p<0.01), M3-variant subtype (11% vs 4%, p=0.02), fibrinogen <170 mg/dl (7% vs 3%, p=0.02) and hemoglobin >10 g/dl (8% vs 4%, p=0.03). No significant relation was observed with CD2 or other surface antigens, as well as FLT3 mutations. Use of tranexamic acid showed a trend towards a higher incidence of thrombosis (6% vs 3%, p=0.08). In multivariate analysis hypofibrinogenemia and M3-v subtype remained as independent prognostic factors. Thrombosis was related with a higher induction mortality (including deaths before start of CT), 28% vs 11%, p<0.01. Conclusion: Thrombo-ischemic events are relatively frequent in active APL patients implying an elevated early mortality. Hypofibrinogenemia and M3-v are associated with a higher incidence of thrombosis. Treatment with tranexamic acid has not decreased hemorrhagic mortality and it could be related to increased thrombotic events. Therefore its prophylactic use should not be recommended.

C0321: Risk Factors for Thrombosis in Acute Promyelocytic Leukemia

2014 ◽  
Vol 133 ◽  
pp. S104-S105
Author(s):  
M. Mitrovic ◽  
N. Suvajdzic ◽  
I. Elezovic ◽  
A. Bogdanovic ◽  
V. Dordevic ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia

scholarly journals Validation of a Molecular Risk Score for Prognosis of Patients with Acute Promyelocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1668-1668
Author(s):  
Anna Hecht ◽  
Seraphina Doll ◽  
Heidi Schaarschmidt ◽  
Daniel Nowak ◽  
Verena Nowak ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Promyelocytic Leukemia ◽  
Risk Score ◽  
Validation Cohort ◽  
Conflicts Of Interest ◽  
Wilms Tumor ◽  
Promyelocytic Leukemia ◽  
Outcome Analysis ◽  
Original Cohort ◽  
Expression Levels

Abstract Introduction: Risk stratification in acute promyelocytic leukemia (APL) is based on clinical parameters, namely leukocyte and platelet counts at initial diagnosis as combined in the Sanz Score. However, during the last years the influence of additional molecular genetic markers on prognosis of APL patients has been postulated. In 2015 we published the results of a molecular risk score integrating expression data of the genes brain and acute leukemia, cytoplasmic (BAALC), ets' related gene (ERG) and Wilms' Tumor 1 (WT1) with strong independent influence on outcome and relapse risk of APL patients treated in the German AMLCG studies (Hecht et al., Leuk Res 2015). The aim of our study was to validate our data in an independent patient cohort. Methods: In cooperation with the German SAL (Study Alliance Leukemia) group we obtained a validation set of samples of mononuclear cells derived from the bone marrow of 76 patients with confirmed diagnosis of APL prior to therapy. The validation cohort consisted of 37 female and 39 male patients with a median age of 50 years (range 20-82 years; Table 1). Patients were diagnosed and treated between 2000 and 2014 mostly with an ATRA plus Idarubicin based induction therapy followed by Sanz score-dependent consolidation and maintenance chemotherapy. RNA was extracted using the AllPrep DNA/RNA Mini Kit and cDNA was synthesized using 500µg of RNA with a QuantiTect Reverse Transcription Kit (both Qiagen, Hilden, Germany). Expression levels of BAALC, ERG and WT1 were then analyzed using quantitative real-time RT-PCR with the same conditions and primers as used in the original test cohort and the same calibrator cDNA from cell lines was used for the analysis. The following gene expression levels were defined as negative risk factors in preceding studies: BAALC expression ≥25th percentile (BAALChigh), ERG expression ≥75th percentile (ERGhigh) and WT1 expression ≤25th percentile or ≥75th percentile (WT1low or high). The integrative risk score was calculated as described before: For the presence of one of the mentioned risk factors, one scoring point was assigned to a respective patient, i.e. a maximum of 3 points (one point for BAALChigh, ERGhigh and WT1low or high, respectively) and a minimum of 0 points (i.e. presenting with none of the aforementioned risk factors). Overall survival (OS), relapse free survival (RFS) and cumulative incidence of relapse (CIR) were calculated using the Kaplan-Meier method. Results: The expression of the three genes BAALC, ERG and WT1 compared to healthy controls were exactly the same as in the original cohort. Application of the molecular risk score on APL patients of the validation cohort clearly discriminated patients according to their risk comparable to the original APL cohort (Figure 1). Patients with 0 points had a very good prognosis with no deaths or relapses, whereas patients with 3 points (i.e. concurrent presence of all three risk factors) had a very poor outcome with an OS of 51%, a RFS of 50% and a CIR of 38%. The differences between patients with 1 and 2 points were less pronounced in the validation cohort. However, the statistical analyses in the validation cohort did not yield significance. As the main reason we assume that the validation cohort altogether showed a significantly improved OS and RFS compared to the original cohort which was treated a decade earlier, so differences between the subgroups could not be that pronounced. For both cohorts stratification by the Sanz Score did not show significant differences in outcome (analysis for RFS p=0.46 in original cohort and p=0.44 in validation cohort). Conclusion: A validated molecular-based integrative risk score was able to define subgroups of APL patients with different outcome independently of the Sanz score. The validation of the strong influence of the combination of molecular risk factors is particularly interesting as the new analyses of the three genes BAALC, ERG and WT1 separately did not confirm the strong results of the single analyses of each gene. The discrimination of patients according to the risk score is evident though. This argues for their integration in future studies. Figure 1 Comparison of the original cohort and the validation cohort. Discrimination by the integrative risk score (0-3points) for OS, RFS and CIR. Figure 1. Comparison of the original cohort and the validation cohort. Discrimination by the integrative risk score (0-3points) for OS, RFS and CIR. Disclosures No relevant conflicts of interest to declare.

scholarly journals Risk factors of thrombosis in chinese subjects with acute promyelocytic leukemia

2021 ◽  
Author(s):  
Xueya Zhang ◽  
Xizhe Guo
Keyword(s):  
Risk Factors ◽  
Acute Promyelocytic Leukemia ◽  
Detection Rate ◽  
Disease Risk ◽  
Laboratory Data ◽  
Female Gender ◽  
Promyelocytic Leukemia ◽  
Rare Manifestation ◽  
Chinese Subjects ◽  
Pai 1

Abstract Acute promyelocytic leukemia (APL) is a kind of malignant hematologic disease. Thrombosis is a rare manifestation of APL. However, the risk factors of thrombosis related to chinese APL patients are not fully understood. Clinical and laboratory data of 44 consecutively chinese APL patients were collected and analyzed. 1 arterial and 6 venous thrombosis occurred in 44 patients, including 22 males and 22 females, with a median age of 44 years (range 18–74 years). The ratio of male and female gender (P = 0.68), age (P = 0.823), white blood cell count (P = 0.077), hemoglobin (P = 0.409), platelets (P = 0.334), disease risk stratification (P = 0.475), CD2 (P = 0.737), khorana score (P = 0.52), differentiation syndrome (DS) (P = 0.562) and gene mutation related to prognosis of APL, including DNMT3A (P = 0.44), TET2 (P = 0.43), IDH1 (P = 0.6), IDH2 (P = 0.66), NRAS (P = 0.66), ASXL1(P = 0.9) in the two groups with and without thrombosis were not statistically significant. The detection rate of PAI-1 genotype 4G4G was 71.4% (5/7) in 7 patients with thrombosis, while the detection rate of PAI-1 genotype 4G4G in 37 patients without thrombosis was 8.1% (3/37). The differences between the two groups in WT-1 (P = 0.01), PAI-1 4G4G (P = 0.0009), bcr3 (P = 0.027), CD15 (P = 0.005), and FLT3-ITD mutation (P = 0.0008) were statistically significant. The results suggested the PAI-1 gene 4G4G type, PML/RARa (bcr3), CD15, WT-1 and FLT3-ITD mutations excluding DNMT3A, TET2, IDH1/2, NRAS and ASXL1 are risk factors of thrombotic events in chinese APL patients.

scholarly journals Risk factors of thrombosis in Chinese subjects with acute promyelocytic leukemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xueya Zhang ◽  
Xizhe Guo
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Acute Promyelocytic Leukemia ◽  
Detection Rate ◽  
Disease Risk ◽  
Laboratory Data ◽  
Female Gender ◽  
Promyelocytic Leukemia ◽  
Increased Risk ◽  
Pai 1

Abstract Background Acute promyelocytic leukemia (APL) is a special type of acute myeloid leukemia Thrombosis is at increased risk complication in patients with this disease. However, the risk factors of thrombosis related to Chinese APL patients are not fully understood. Methods In this study, clinical and laboratory data of 44 consecutively Chinese APL patients were collected and analyzed. Results One arterial and 6 venous thrombosis occurred in 44 patients, including 22 males and 22 females, with a median age of 44 years (range from 18 to 74 years). The ratio of male and female gender, age, white blood cell count, hemoglobin, platelets, disease risk stratification, CD2, Khorana score, differentiation syndrome (DS) and gene mutation related to prognosis of APL, including DNMT3A, TET2, IDH1, IDH2, NRAS and ASXL1 in the two groups with and without thrombosis were not statistically significant. The detection rate of PAI-1 genotype 4G4G was 71.4% (5/7) in 7 patients with thrombosis, while the detection rate of PAI-1 genotype 4G4G in 37 patients without thrombosis was 8.1% (3/37). The differences between the two groups in WT-1 (P = 0.01), PAI-1 4G4G (P = 0.0009), bcr3 (P = 0.027), CD15 (P = 0.005), and FLT3-ITD mutation (P = 0.0008) were statistically significant. Using multivariate analysis, the risk factors of venous thrombosis in APL were CD15 (P = 0.043), PAI-1 4G4G (P = 0.009), WT-1 (P = 0.043) and FLT3/ITD (P = 0.013), respectively. Conclusion Our results suggested the PAI-1 gene 4G4G type, CD15, WT-1 and FLT3-ITD mutations excluding DNMT3A, TET2, IDH1/2, NRAS and ASXL1 are risk factors of thrombotic events in Chinese APL patients.

An Optimized Risk Stratification Model in Acute Promyelocytic Leukemia Identifies Patients with an Exceptionally Good Prognosis Regarding the Incidence of Relapse

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 72-72
Author(s):  
Anna Hecht ◽  
Daniel Nowak ◽  
Verena Nowak ◽  
Benjamin Hanfstein ◽  
Thomas Büchner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Factors ◽  
Multivariate Analysis ◽  
Risk Stratification ◽  
Acute Promyelocytic Leukemia ◽  
Risk Score ◽  
Risk Groups ◽  
Promyelocytic Leukemia ◽  
Expression Levels ◽  
Therapeutic Decisions

Abstract Introduction: Risk stratification in acute promyelocytic leukemia (APL) is based on the easily accessible Sanz-Score, which combines leukocyte and platelet counts at initial diagnosis. This score showed significant differences in relapse-free survival (RFS) of APL patients in various studies and is currently used to determine whether a patient can be treated with ATRA and ATO alone or needs additional chemotherapy. However, to make therapeutic decisions based on a risk stratification system derived from the endpoint RFS bears the drawback that relapses are rare in APL and most events are deaths in complete remission (CR), which can be therapy related (e.g. toxicity). The cumulative incidence of relapse (CIR) therefore seems to be a better parameter for decision making with regard to therapy intensity. In this study, we optimized a risk score combining data on gene expression of BAALC (brain and acute leukemia, cytoplasmic), ERG (ets’ related gene) and WT1 (Wilms’ tumor 1) to retrospectively predict the CIR of APL patients. Methods: Data on BAALC, ERG and WT1 expression levels of 79 patients with newly diagnosed APL were obtained from bone marrow mononuclear cells using quantitative real-time RT-PCR in preceding studies. The following gene expression levels were identified as negative risk factors: BAALC expression ≥25th percentile (BAALChigh), ERG expression >75th percentile (ERGhigh) and WT1 expression ≤25th percentile or ≥75th percentile (WT1low or high). As ERGhigh was the only independent predictor for relapse in multivariate analysis with a hazard ratio (HR) of 11.6, its predictive weight was regarded superior, respectively . Cut-off analyses were performed to determine the optimal ERG expression level cut-off for risk of relapse. Accordingly, the new cut-off for high ERG expression was set at ≥62nd percentile (optimized ERGhigh: optERGhigh; Sensitivity: 1.0, Specificity: 0.71). A combined risk score was developed as follows: For the presence of one of the mentioned risk factors, one scoring point was assigned to a respective patient, i.e. a maximum of 3 points (one point for BAALChigh, optERGhigh and WT1low or high, respectively) and a minimum of 0 points (i.e. presenting with none of the aforementioned risk factors) could be allocated to one patient. Accordingly, patients were divided into two risk groups: 34 patients scored 0-1 points and 45 patients scored 2-3 points. CIR, overall survival (OS) and RFS were calculated using the Kaplan-Meier method and a log-rank test was used to compare differences between the two risk groups (p<0.05). Results: Patients with 2-3 points had a CIR of 18% at 10 years of follow-up whereas none of the patients with 0-1 points suffered a relapse (CIR: 0%; p=0.02; Fig. 1). All relapses occurred between 8.4 months and 3.5 years after first CR. Moreover, OS and RFS also differed significantly between the two risk groups: OS was 53% for patients with 2-3 points vs. 85% for patients with 0-1 points (p=0.004); RFS was 49% vs. 93%, respectively (p<0.0001). In multivariate analysis the optimized combined risk score was the strongest independent risk factor for every endpoint. Conclusion: The combination of expression levels of BAALC, ERG and WT1 into a risk score identified a group of patients at high risk for relapse which could benefit from close monitoring resulting possibly in an early intervention when molecular relapse is detected. On the other hand, it identified a low risk group with very good outcome and no APL-related events after patients had achieved first CR. A molecular risk score focusing on relapse risk might be a promising approach to guide therapeutic decisions in the future. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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