Dalteparin Thromboprophylaxis in Cancer Patients at High Risk for Venous Thromboembolism: A Randomized Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 427-427 ◽  
Author(s):  
Alok A. Khorana ◽  
Charles W. Francis ◽  
Nicole Kuderer ◽  
Marc Carrier ◽  
Thomas L. Ortel ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
High Risk ◽  
Board Of Directors ◽  
Cancer Patients ◽  
Research Funding ◽  
Primary Efficacy ◽  
Advisory Committees ◽  
Intention To Treat ◽  
Efficacy Outcome ◽  
Risk Patients

Abstract Background: Ambulatory cancer patients at high-risk for venous thromboembolism (VTE) can be identified using a validated risk score. We evaluated the benefit of outpatient thromboprophylaxis with dalteparin in such high-risk patients in a multicenter randomized controlled trial. Methods: Cancer patients at high risk for VTE (Khorana score ≥3) and initiating a new systemic chemotherapy regimen were screened for VTE and, if negative, randomized to either dalteparin 5000 units daily subcutaneously or no prophylactic anticoagulation for 12 weeks. Subjects in both arms were screened with lower extremity ultrasounds every 4 weeks on study. Primary efficacy endpoint was any VTE over 12 weeks and primary safety endpoint was clinically relevant bleeding events over 13 weeks. The study was terminated due to poor accrual. Results: Of 117 enrolled patients, 19 were not randomized due to the presence of VTE on initial screening (N=10, 8.5%) or for other reasons (N=9). The mean age was 59 years with 46% female and 54% male, similar in both arms. The most common primary sites of cancer were pancreas, gastro-esophageal junction, lung and lymphoma. Over three-fourths of patients in each arm had an ECOG performance status of 0 or 1.Of 98 patients randomized, VTE occurred in 12% (N=6/50) of patients on the dalteparin arm and 21% (N=10/48) on the control arm (hazard ratio, HR 0.69, 95% CI 0.23-1.89) (absolute risk reduction 9%, relative risk reduction 42%, number needed to treat = 12). Major bleeding was similar (N=1) in each arm but clinically relevant bleeding was higher in the dalteparin arm (N=7 versus 1 in the control arm) (HR = 7.0, 95% CI 1.2-131.6). There was no difference in overall survival. Conclusions: Thromboprophylaxis is associated with a non-significant reduced risk of VTE with no effect on major bleeding or survival but increased risk of clinically relevant bleeding in this underpowered study population. The Khorana score successfully identifies patients with high incidence of VTE both at baseline and during study. The high incidence of baseline VTE suggests that consideration should be given to screening high-risk patients in clinical practice prior to starting systemic therapy. Future studies should continue to focus on risk-adapted approaches to reduce the burden of VTE in cancer. (Funded by NIH/NHLBI R01HL095109; clinicaltrials.gov identifier: NCT00876915). Table 1. Baseline Characteristics of Patients Enrolled in the PHACS trial Dalteparin Observation Total Enrolled (n) Baseline VTE, n (%) DVT PE Other reasons for not randomizing Randomized (n) Age, mean (SD), y --- --- --- --- --- 50 60 (10) --- --- --- --- --- 48 58 (12) 117 10 (9%) 6* (5%) 4 (3%) 9 98 59 (11) Gender, n (%) Female 21 (42%) 24 (50%) 45 (46%) Male 29 (58%) 24 (50%) 53 (54%) Primary Tumor Site, No. (%) Gynecologic 4 (8%) 4 (8%) 8 (8%) Colorectal 1 (2%) 3 (6%) 4 (4%) GE junction 8 (16%) 4 (8%) 12 (25%) Lung 6 (12%) 7(15%) 13 (27%) Genitourinary 2 (4%) 0 (0%) 2 (2%) Lymphoma 5 (10%) 2 (4%) 7 (15%) Breast 1 (2%) 1 (2%) 2 (2%) Pancreatic 19 (38%) 17 (35%) 36 (37%) Gastric 4 (8%) 6 (13%) 10 (10%) Other 0 (0%) 4 (8%) 4 (4%) Previous history of VTE, n (%) 4 (8%) 2 (4%) 6 (6%) *NOTE: 1 subject had both DVT and PE at baseline screening Abbreviations: DVT, deep vein thrombosis; PE pulmonary embolism; VTE, venous thromboembolism; ECOG: Eastern Cooperative Oncology Group Figure 1. Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm. Figure 1. Cumulative Incidence Curves for the Primary Efficacy Outcome in the Intention-to-Treat Population, According to Study Arm. Disclosures Khorana: Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; sanofi: Consultancy, Honoraria. Off Label Use: Randomized trial of dalteparin as prophylaxis. The drug is approved for treatment of cancer-associated thrombosis but not for prophylaxis.. Francis:Eisai: Consultancy, Research Funding; Portola: Consultancy, Honoraria; NHLBI: Consultancy; Lilly: Consultancy. Kuderer:Hospira: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy. Carrier:Leo Pharma: Consultancy, Research Funding; BMS: Research Funding; Bayer: Consultancy, Honoraria; Pfizer: Consultancy. Ortel:Instrumentation Laboratory: Consultancy; Instrumentation Laboratory: Research Funding; Eisai: Research Funding; Daiichi Sankyo: Consultancy. Wun:Janssen: Consultancy. Iyer:Ipsen Pharmaceuticals: Consultancy; Genentec: Research Funding; Bristol Myers Squibb: Honoraria. Lyman:Amgen: Research Funding.

Risk Stratification for the Development of Venous Thromboembolism in Hospitalized Patients with Cancer

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4728-4728 ◽  
Author(s):  
Arabesque Parker ◽  
Erica A. Peterson ◽  
Agnes Y. Y. Lee ◽  
Carine de Wit ◽  
Marc Carrier ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
High Risk ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Research Funding ◽  
Low Risk ◽  
Advisory Committees ◽  
Risk Patients

Abstract Introduction: No method of venous thromboembolism (VTE) risk stratification exists for hospitalized cancer patients. The Khorana score is a validated tool in outpatients with cancer. The objective of this study was to assess the Khorana score for predicting development of VTE in cancer patients during admission to hospital. Methods: We conducted a retrospective analysis of data collected from healthcare records of consecutive, medically-ill cancer patients hospitalized between January and June 2010 in 3 academic medical centers in Canada. Objectively diagnosed symptomatic VTE during hospitalization, anticoagulant thromboprophylaxis (TP), and Khorana score variables were collected for every patient. Patients receiving therapeutic anticoagulation at admission, and those with incomplete data were excluded. The risk of VTE based on Khorana score category was evaluated using logistic regression. Continuous data were compared using a Student's t-test and expressed using the means and standard deviations. Categorical data were compared using the Pearson Chi-square test and were expressed as percentages. Statistical significance was defined as alpha less than 0.05. Results: 1398 patients were included. Mean age was 61.6 years, 51.2% were male, and mean BMI was 25.9 kg/m2. The most frequent tumor types were non-small cell lung carcinoma (12.7%) followed by lymphoma (10.9%). The median length of stay was 6 days (range 0-114 days). The most frequent reasons for hospitalization were chemotherapy (22.3%) followed by pain and palliation (21.4%). 34.5% received anticoagulant TP (n = 483/1398). The incidence of VTE was 2.9% (41/1398) overall, 5.4% (9/166) in high, 3.2% (26/817) in moderate, and 1.4% (6/415) in low Khorana score risk groups. High risk patients were significantly more likely than low risk patients to have VTE (p=0.016; OR 3.9, 95% CI 1.4-11.2). There was no difference in VTE incidence between patients who received anticoagulant TP and those who did not (3.5% vs 2.6%, p = 0.345). Patients with high risk Khorana score were more likely to receive anticoagulant TP than those with low risk Khorana score (46.4% vs. 23.9%, p <0.001, OR 2.8, 95% CI 1.9-4.0). Total incidence of major bleeding was 1.8% (25/1398). There was no difference in major bleeding between patients who received anticoagulant TP and those who did not (1.7% vs. 1.9%, p = 0.787). Conclusion: The Khorana score is predictive of VTE development in cancer patients who are hospitalized for medical illness and may be a useful tool for tailoring inpatient anticoagulant prophylaxis. Disclosures Lee: LEO: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Carrier:BMS: Research Funding; Leo Pharma: Research Funding. Wu:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Two Doses of Apixaban for the Extended Treatment of Venous Thromboembolism

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. LBA-1-LBA-1 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Harry Roger Buller ◽  
Alexander Cohen ◽  
Madelyn Curto ◽  
Alexander S. Gallus ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Major Bleeding ◽  
Research Funding ◽  
Primary Efficacy ◽  
Advisory Committees ◽  
Primary Efficacy Outcome ◽  
Extended Treatment ◽  
Safety Outcome ◽  
Efficacy Outcome

Abstract Abstract LBA-1 Background: Apixaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for extended treatment of venous thromboembolism. Objectives: To compare the efficacy and safety of two doses of apixaban (2.5 or 5 mg twice daily) with placebo for the extended treatment of venous thromboembolism in patients who have completed 6 to 12 months of prior anticoagulant therapy. Methods: This randomized, double-blind study (ClinicalTrials.gov number, NCT00633893) compared two apixaban doses (2.5 or 5 mg twice daily) with placebo for 12 months in patients with venous thromboembolism who had completed 6–12 months of anticoagulation. The primary efficacy outcome was symptomatic recurrent venous thromboembolism or all-cause mortality. Secondary efficacy outcomes included (a) the composite of symptomatic venous thromboembolism or venous thromboembolism-related death, and (b) the composite of symptomatic venous thromboembolism, venous thromboembolism-related death, myocardial infarction, stroke, or cardiovascular-related death. The primary safety outcome was major bleeding; the secondary safety outcome was major and clinically relevant non-major bleeding. Results: The study included 2486 patients: 829, 840, and 815 randomized to placebo, apixaban 2.5 mg, and apixaban 5 mg, respectively. Rates of the primary efficacy outcome were 11.6% in the placebo group, compared with 3.8% and 4.2% in the apixaban 2.5 mg and 5 mg groups, respectively (absolute risk differences of 7.8% and 7.4%, respectively; 95% confidence intervals 5.3% to 10.3% and 4.8% to 10%, respectively; p<0.001 for both comparisons). Other outcomes are detailed in the Table. Conclusions: Both doses of apixaban reduced the risk of symptomatic recurrent fatal or non-fatal venous thromboembolism by approximately 80% without increasing the rate of major bleeding. In addition, both apixaban doses reduced arterial thrombotic events. The lower apixaban dose may be preferred for extended treatment, because of the trend for less clinically relevant non-major bleeding. Disclosures: Agnelli: Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy; Bayer Healthcare: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Buller:Bayer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-aventis: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Isis: Consultancy, Research Funding; Thrombogenics: Consultancy, Research Funding. Cohen:Astellas: Consultancy, Research Funding; AstraZenica: Consultancy, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boheringer-Ingelheim: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mitsubishi Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Schering Plough: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Curto:Pfizer: Employment. Gallus:Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Bayer: Membership on an entity’s Board of Directors or advisory committees; boehringer-Ingelheim: Membership on an entity’s Board of Directors or advisory committees. Johnson:Pfizer: Employment. Porcari:Pfizer: Employment. Raskob:Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myer Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy; Quintiles: Consultancy; National Blood Clot Alliance: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Weitz:Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1565-1565 ◽  
Author(s):  
Patrizia Mondello ◽  
Irene Dogliotti ◽  
Jan-Paul Bohn ◽  
Federica Cavallo ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with &gt;90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= &lt;0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS &lt;3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Novel Prognostic Model That Is Superior to FLIPI-1 and FLIPI-2 and Integrates Clinical and Treatment Factors to Predict Progression-Free Survival and Early Treatment Failure in Patients with Follicular Lymphoma in the GALLIUM Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2872-2872 ◽  
Author(s):  
Farheen Mir ◽  
Andrew Grigg ◽  
Michael Herold ◽  
Wolfgang Hiddemann ◽  
Robert Marcus ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Model ◽  
Low Risk ◽  
Prognostic Variables ◽  
Advisory Committees ◽  
High Risk Disease ◽  
Risk Patients ◽  
Equity Ownership

Abstract Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

scholarly journals Revised-MALT-IPI: A New Predictive Model That Identifies High-Risk Patients with Extranodal Marginal Zone Lymphoma (EMZL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4010-4010
Author(s):  
Juan Pablo Alderuccio ◽  
Isildinha M Reis ◽  
Thomas M. Habermann ◽  
Brian K. Link ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
High Risk ◽  
Family Member ◽  
Board Of Directors ◽  
Risk Score ◽  
Research Funding ◽  
Stage Iii ◽  
Advisory Committees ◽  
High Risk Patients ◽  
Disease Characteristics ◽  
Risk Patients

INTRODUCTION: EMZL is a heterogeneous disease with variable risk for relapse and progression. Based on age ≥70 years, stage III-IV and elevated LDH, Thieblemont et al (Blood. 2017) developed the MALT-IPI to identify high-risk patients. In this index, disease characteristics (stage and LDH) account for 66% while a disease nonspecific characteristic (age) for 33% of the index score. We reported (Am J Hematol. 2019) that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival and increased incidence of higher grade transformation. To better recognize disease-attributable high-risk patients, we developed a new EMZL prognosis score chiefly based on patient's disease characteristics. METHODS: The revised (R)-MALT-IPI was developed using a retrospective data set of 405 EMZL patients treated at the University of Miami (UM) from 1995 to 2017. Cox proportional hazards regression analysis was conducted to evaluate the effect of the potential prognostic variables on progression-free survival (PFS) and overall survival (OS) and to develop the new index R-MALTI-IPI based on PFS. Model validation was performed in two independent cohorts of EMZL patients from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) database (n=297) and the IELSG-19 study (n=400) used for the development of MALT-IPI. Performance of various prognostic indices was compared using AIC statistics, and concordance c-statistics by Harrell (CH) and by Gonen and Heller (CGH). RESULTS: Among the candidate variables tested in univariable analysis, the following were statistically significant predictors of shorter PFS: age >60, age ≥70, anemia (Hb<12g/dL), stage III-IV, ECOG PS ≥2, elevated serum LDH, number of extranodal sites >1, number of nodal sites >4, and presence of MMS at diagnosis, defined as EMZL with ≥2 different extranodal sites excluding spleen and bone marrow. A stepwise Cox regression analysis yielded a multivariable model with four independent predictors of shorter PFS: age >60 (HR=1.53, p=0.010), elevated LDH (HR=1.73, p=0.004), stage III-IV (HR=2.03, p=0.0003) and presence of MMS (HR=2.78, p<0.0001). Based on this, a new index R-MALT-IPI was developed with scores ranging from 0 to 5, calculated as a sum of 1 point for age >60, elevated LDH, stage III-IV, and 2 points for MMS. The R-MALT-IPI defined 4 risk groups: low-risk (score 0 (35%), reference group), low-medium risk (score 1 (39%), HR=1.91, p=0.005), medium-high risk (score 2 (13%), HR=3.77, p<0.0001), and high-risk (score 3+ (13%), HR=8.54, p<0.0001). When compared with MALT-IPI, R-MALT-IPI better stratifies and separates high risk patients (26%) into medium-high risk and high-risk patients with a median PFS of 5.8 years (2.9-9.1) and 1.8 years (1.3-2.6) respectively, compared to 2.6 years (1.8-4.7) in the high-risk MALT-IPI patients (16.8%). The R-MALT-IPI index also distinguished patients with different OS. For validation, we analyzed R-MALT-IPI index performance in independent Iowa/Mayo Clinic MER and IELSG-19 cohorts. Both R-MALT-IPI and MALT-IPI were useful in distinguishing PFS and OS in all the cohorts. In the UM training cohort, the concordance c-statistics' values for the two indices were similar: for PFS, CH=0.6893 and CGH=0.6611 for R-MALT-IPI, and CH=0.6551 and CGH=0.6367 for MALT-IPI; for OS, CH=0.7017 and CGH=0.6813 for R-MALT-IPI, and CH=0.7029 and CGH=0.67715 for MALT-IPI. In the validation cohorts, the concordance c-statistics' values for the two indices were also similar, but slightly lower than in the UM cohort for PFS. When comparing medium-high to high-risk R-MALT-IPI groups, there was a reduction of 4 years in median PFS in the UM cohort, and reduction in median EFS of 5.6 years in the MER cohort, an important difference between these risk groups identified by the R-MALT-IPI index. CONCLUSIONS: R-MALT-IPI is a new index for EMZL centered principally on disease characteristics. Overall, there is a similar prediction of PFS (EFS) by R-MALT-IPI and MALT-IPI indexes; however, R-MALT-IPI better recognizes a high-risk group accounting for 13% of EMZL patients with short median PFS and thus obviates the waiting period needed to recognize patients with shorter EFS24. Collaborative studies addressing best treatment approach for these high-risk EMZL patients are eagerly needed. Disclosures Alderuccio: Agios: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; OncLive: Consultancy; Targeted Oncology: Honoraria; Puma Biotechnology: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member. Thieblemont:Cellectis: Membership on an entity's Board of Directors or advisory committees; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Zucca:Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees.

Venous Thromboembolism (VTE) Prevention with Semuloparin in Cancer Patients Initiating Chemotherapy: Benefit-Risk Assessment by VTE Risk in SAVE-ONCO

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 206-206 ◽  
Author(s):  
Daniel George ◽  
Giancarlo Agnelli ◽  
William Fisher ◽  
Ajay Kakkar ◽  
Michael R Lassen ◽  
...  
Keyword(s):  
Risk Assessment ◽  
High Risk ◽  
Board Of Directors ◽  
Cancer Patients ◽  
Research Funding ◽  
P Value ◽  
Advisory Committees ◽  
Benefit Risk Assessment ◽  
Bayer Healthcare ◽  
High Risk Cancer

Abstract Abstract 206 Background: Cancer patients receiving chemotherapy are at increased risk for VTE. Recent oncology guidelines emphasize the need for randomized studies with VTE risk assessment in these patients (Streiff MB, et al. JNCCN. 2011;9:714–777). Semuloparin is a new ultra-low-molecular-weight heparin with high anti-factor Xa and minimal anti-factor IIa activities. The SAVE-ONCO study investigated semuloparin vs placebo for VTE prevention in cancer patients receiving chemotherapy. Methods: Patients with metastatic or locally advanced cancer of lung, pancreas, stomach, colon-rectum, bladder or ovary initiating a chemotherapy course, were randomized to once-daily subcutaneous semuloparin 20 mg or placebo until change of chemotherapy. The primary efficacy outcome was a composite of symptomatic deep-vein thrombosis, any non-fatal pulmonary embolism, or VTE-related death. The main safety outcome was clinically relevant bleeding (major and non major). Baseline VTE risk was assessed by a score specifically developed and validated in chemotherapy-treated cancer patients (Khorana AA, et al. Blood. 2008;111:4902–7). According to this predictive model a score of 2 was assigned to very high-risk cancer sites (pancreatic or gastric), a score of 1 was assigned to high-risk cancer sites (lung, ovarian, or bladder cancer) and 1 is added to the score for each of the following parameters: platelet count ≥350 × 109/L, hemoglobin <10 g/dL and/or use of erythropoietin-stimulating agents, leukocyte count >11 × 109/L, and body mass index ≥35 kg/m2. Results: Among the 3212 patients randomized, the majority had lung (36.6%) or colorectal (28.9%) cancer and approximately two-thirds had metastatic cancer. In total, 550 (17.4%) of patients enrolled were at high risk of VTE, 1998 (63.2%) were at moderate risk, and 614 (19.4%) were at low risk (VTE risk score of ≥ 3, 1–2, or 0 points, respectively). All risk groups were well balanced between the treatment groups. Median treatment duration was approximately 3.5 months. Overall, semuloparin significantly reduced VTE or VTE-related death by 64% (p<0.0001; Table) vs placebo. The treatment effect was consistent across various levels of VTE risk (interaction p-value=0.6048; Table). Clinically relevant bleeding occurred in 2.8% and 2.0% of the patients in the semuloparin and placebo groups, respectively (Table). The incidence of major bleeding was similar: 1.2% and 1.1% patients in the semuloparin and placebo groups, respectively (hazard ratio [HR] 1.05; 95% confidence interval [CI] 0.55–1.99). No increased incidence of clinically relevant bleeding was observed with semuloparin vs placebo across various levels of VTE risk (interaction p-value=0.9409; Table). Conclusions: In cancer patients receiving chemotherapy, thromboprophylaxis with semuloparin was consistently associated with a favorable benefit-risk profile across various levels of VTE risk, but greatest in moderate to high risk patients. Antithrombotic prophylaxis should be considered in patients with cancer receiving chemotherapy, particularly in those who are at moderate to high risk of VTE. Disclosures: George: Viamet: Consultancy, Research Funding; Sanofi: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Medivation: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Ipsen: Consultancy, Research Funding; Genentech/Roche: Consultancy, Speakers Bureau; Dendreon: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy; Astellas: Consultancy; GSK: Research Funding, Speakers Bureau; BMS: Research Funding; Exelixis: Research Funding. Agnelli:GlaxoSmithKline: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; sanofi-aventis: Honoraria. Fisher:Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; sanofi-aventis: Honoraria, Research Funding. Kakkar:Bayer HealthCare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARYx Therapeutics: Consultancy; Canyon: Consultancy; GlaxoSmithKline: Honoraria. Lassen:Astellas Pharma Europe: Consultancy; Bayer HealthCare AG: Consultancy; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; GlaxoSmithKline: Consultancy; Merck Serono: Consultancy; Pfizer: Consultancy; Protola Pharma: Consultancy; sanofi-aventis: Consultancy. Mismetti:sanofi-aventis: served as a member of Steering Committees. Mouret:Bayer HealthCare: Consultancy, Honoraria; sanofi-aventis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Lawson:Sanofi: Employment. Turpie:Astellas Pharma Europe: Consultancy; Bayer HealthCare AG: Consultancy; Portola Pharma: Consultancy; sanofi-aventis: Consultancy.

Comparison Of Conventional, FISH and GEP Prognostic Factors In Multiple Myeloma: Introducing a Novel Risk Stratification

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3092-3092 ◽  
Author(s):  
Rowan Kuiper ◽  
Martin van Vliet ◽  
Annemiek Broyl ◽  
Yvonne de Knegt ◽  
Bronno van der Holt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Risk ◽  
Partial Likelihood ◽  
Data Sets ◽  
Advisory Committees ◽  
Risk Patients

Abstract Introduction Multiple Myeloma (MM) is a heterogeneous disease with highly variable survival. Gene expression profiling (GEP) classifiers, such as the EMC-92, can consistently distinguish high risk patients from standard risk patients. Other prognostic factors for MM include the international staging system (ISS) and FISH. Here we present a comparison of prognostic factors and introduce a novel stratification based on EMC-92 and ISS. Methods Scores were calculated for the GEP classifiers EMC-92, UAMS-70, UAMS-17, UAMS-80 and MRC-IX-6 for the following five studies: HOVON-65/GMMG-HD4 (n=328; GSE19784), MRC-IX (n=247; GSE15695), UAMS-TT2 (n=345; GSE2658), UAMS-TT3 (n=238; E-TABM-1138 and GSE2658) and APEX (n=264; GSE9782; for details, see Kuiper R, et al. Leukemia (2012) 26: 2406–2413). FISH data were available for the HOVON-65/GMMG-HD4 trial and the MRC-IX trial. ISS values were available for all datasets except UAMS-TT2. Univariate associations between markers and overall survival (OS) were investigated in a Cox regression analysis, using Bonferroni multiple testing correction. For pair wise analysis of markers, the significance in the increase of partial likelihood was calculated. In order to find the strongest combination (defined as the highest partial likelihood) of GEP-ISS, we compared these pair-wise on the same data. Training sets of classifiers were excluded for those analyses in which that specific classifier was tested. All survival models have been stratified for study. The calculations were done in R using the package survival. Results Prognostic value of FISH, GEP and serum markers was determined in relation to overall survival (Figure 1). GEP classifiers generally performed much better than FISH markers. Of 6 FISH markers with known adverse risk, del(17p), t(4;14), t(14;20) and del(13q) demonstrated a significant association only in one of two data sets with available FISH (HOVON-65/GMMG-HD4). GEP classifiers, on the other hand, are much more robust. Classifiers EMC-92, UAMS-70 and UAMS-80 significantly identify a high-risk population in all evaluated data sets, whereas the UAMS-17 and the MRC-IX-6 classifiers predict high-risk patients in three of four datasets. As expected, ISS staging demonstrated stable and significant hazard ratios in most studies (three out of four). Indeed, when evaluating a merged data set, both ISS and all evaluated GEP classifiers are strong prognostic factors independent of each other. Markers with additive value to each other include all combinations of GEP classifiers as well as the combination of GEP classifiers together with ISS. Tested in independent sets, the EMC-92 classifier combined with ISS is the best combination, as compared to other classifier-ISS combinations tested on the same independent data sets. The strongest risk stratification in 3 groups was achieved by splitting the EMC-92 standard risk patients into low risk, based on ISS stage I, and intermediate risk, based on ISS stage II and III. This stratification retains the original EMC-92 high-risk group, and is robust in all cohorts. The proportions of patients defined as low, intermediate and high risk for this combined EMC-92-ISS classifier are 31% / 47% / 22 % (HOVON-65/GMMG-HD4), 19% / 61% / 20 % (MRC-IX), 46% / 39% / 15 % (UAMS-TT3) and 32% / 55% / 13 % (APEX). Variability in low risk proportion is caused by the variable incidence of ISS stage I. Conclusions We conclude that GEP is the strongest predictor for survival in multiple myeloma and far more robust than FISH. Adding ISS to EMC-92 results in the strongest combination of any of the GEP classifier-ISS combinations. Stratification in low risk, intermediate and high risk may result in improved treatment and ultimately in longer survival of MM patients. This research was supported by the Center for Translational Molecular Medicine (BioCHIP project) Disclosures: van Vliet: Skyline Diagnostics: Employment. Mulligan:Millennium Pharmaceuticals: Employment. Morgan:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van Beers:Skyline Diagnostics: Employment. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding.

Impact of Hypomethylating Agent Therapy in Myelodysplastic Syndromes with Chromosome 3 Abnormalities

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1705-1705
Author(s):  
David Sallman ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Mikkael A. Sekeres ◽  
Amy E. DeZern ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Chromosome 3 ◽  
Advisory Committees ◽  
Monosomy 3 ◽  
Risk Patients

Abstract Background In myelodysplastic syndromes (MDS), abnormalities of chromosome 3 (i.e. inversion 3 (inv(3)), translocation 3q (t(3q)), or deletion 3q (del(3q)) represent a poor-risk karyotype in the Revised International Prognostic Scoring System (IPSS-R). In acute myeloid leukemia (AML) patients with 3q abnormalities, patients with inv(3)/t3;3 represented the most unfavorable group with a median overall survival (OS) of 10.3 months (Lugthart et al., 2010). We previously presented a single institution experience regarding outcomes of MDS patients with chromosome 3 abnormalities. Here, we sought to further define outcomes of chromosome 3 abnormalities in MDS and address the impact of hypomethylating agents (HMA) on outcome in multiple institutions. Patients and Methods Patients were identified through the MDS Clinical Research Consortium and were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality involving chromosome 3. Data analyzed included baseline demographics, disease characteristics, IPSS/IPSS-R scores, treatment and outcome. Responses to HMA therapy were evaluated using International Working Group (IWG) 2006 criteria. Kaplan-Meier estimates were used for overall survival. Results A total of 413 patients were identified with a median age at diagnosis of 67 years. WHO classification was as follows: 9% RA/RARS, 12% RCMD, 26% RAEB-1, 31% RAEB-2, 2% MDS/MPN, 7% MDS Unclassified, 13% AML; 34% had t-MDS. Overall, 97% of patients were higher risk by IPSS-R (i.e., intermediate to very high risk) with a median blast % in bone marrow of 8%. Distribution of cytogenetic abnormalities were inv(3) (10%), del(3q) (12%), t(3q) (18%), monosomy 3 (22%), 3p abnormalities (22%), and other chromosome 3 changes (17%). Median OS for the cohort was 12.0 months (95% C.I. 10.8 to 13.9 months) and 31% of patients without AML transformed to AML. IPSS-R was predictive of median OS across subgroups (P < 0.00001). The specific cytogenetic abnormality was predictive for survival (P < 0.00001) with median OS for t(3q) 19 months, inv(3) 13 months, del(3q) 13 months, 3p 10 months, monosomy 3 9 months, and other 3 abnormalities 11 months. There was no survival difference between patients with translocations of 3q21 versus 3q26 (median OS 18 months versus 18.6 months, P = 0.96). Patients with an isolated chromosome 3 abnormality had significantly improved OS (25.1 months versus 10.9 months (P < 0.00001). Complex karyotype (>/= 3 abnormalities) was observed in 74% of patients and was associated with decreased OS (11 months versus 21 months, P < 0.00001). Of patients who received HMA therapy (48%), the overall response rate was 46% (17% hematological improvement (HI), 7% PR, 20% CR, 2% marrow CR (CRm) with stable disease in 23%). Median OS with and without HMA was 15.5 months versus 8.4 months (p=0.038). In int-2/high risk patients by IPSS, HMA treated patient had a median OS of 14.0 months versus 7.6 months for patients not treated with HMAs (P = 0.005) with no benefit for HMAs in lower-risk patients (median OS 24.5 months with HMA versus 38.7 months without; P =0.41). Cox regression modeling with HMA therapy, IPSS and clinical site confirmed the HMA OS benefit in higher-risk patients (HR 0.69; 95% CI 0.53-0.89; P = 0.005), but showed decreased OS in lower-risk patients (HR 2.0; 95% CI 1.03-3.92; P = 0.04). Allogeneic transplantation was performed in 18% (n=75) of patients, with median OS of 18 months versus 10 months in non-transplanted patients (P < 0.00001). Conclusion In this large cohort of patients with MDS and oligoblastic AML associated with chromosome 3 abnormalities, survival was heterogeneous but overall poor, with isolated chromosome 3 abnormality and t(3q) patients having a more favorable OS than patients with other chromosome 3 anomalies. MDS patients with 3p changes have poor outcomes. Although some patients with chromosome 3 respond to HMA therapy, the overall survival remains poor and novel approaches are needed. Disclosures Sekeres: Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Steensma:Amgen: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Lancet:Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau.

scholarly journals Validation of the Ottawa Score in Cancer Patients with Venous Thromboembolism. the Predicare Cohort Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 167-167 ◽  
Author(s):  
Guy Meyer ◽  
Celine Chapelle ◽  
Philippe Girard ◽  
Florian Scotté ◽  
Anne Lamblin ◽  
...  
Keyword(s):  
Cohort Study ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Research Funding ◽  
Advisory Committees ◽  
Patients With Cancer ◽  
Recurrent Vte ◽  
Support Research

Introduction Venous thromboembolism (VTE) is a difficult to treat condition in patients with cancer with a persisting risk of recurrent VTE during anticoagulant treatment with low-molecular weight heparin (LMWH). Recent data suggest that direct oral anticoagulants (DOACS) are associated with a lower risk of recurrence but a higher risk of bleeding in these patients. Predicting the risk of recurrent VTE with LMWH may help to select the best treatment option. We conducted a prospective multicenter observational cohort study in cancer patients with VTE treated with tinzaparin for 6 months in order to validate the Ottawa score (NCT03099031) and search for additional risk of recurrent VTE. The Ottawa score is composed of 5 variables, female sex (+1), lung cancer (+1), breast cancer (-1) cancer stage 1 (-2) and previous DVT (+1). A score ≤0 is associated with a low risk of recurrent VTE. Methods Adult cancer patients with recent diagnosis of documented symptomatic or incidental VTE (deep vein thrombosis (DVT) or pulmonary embolism (PE) treated with tinzaparin for 6 months were included in the study. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment with tinzaparin. Other endpoints were symptomatic recurrent VTE, major bleeding, heparin induced thrombocytopenia (HIT), all-cause mortality within 3 and 6 months. All events were adjudicated by a Central Adjudication Committee. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. Cumulative incidences were presented with corresponding 95% confidence interval (95% CI). To validate the Ottawa score, the area under the curve (AUC) and its 95% CI were calculated on receiver operating characteristic (ROC) curve analysis; the most discriminant cut-off was then determined by calculating the Youden index. Univariate and multivariate analyses were performed to identify additional predictive factors of recurrent VTE to those included in the Ottawa score using the Fine and Gray method and adjusted on factors included in the Ottawa score. Hazard ratio and their 95% CI were calculated. Results A total of 409 patients were included and analyzed on an intention-to-treat basis; the median age was 68 years and 51% of patients were males. 60.4% of patients had a PE (with or without DVT) .64% received chemotherapy at inclusion or in the month before inclusion. Lung (31.3%) and digestive track (18.3%) cancers were the most common cancer types and 67.0% had stage IV cancers. According to Ottawa score, 58% of patients were classified at high clinical probability of recurrence (score ≥ 1). During the 6 months treatment period, 23 patients had a recurrent VTE, yielding a cumulative incidence of 6.1% (95% CI 4.0-9.3) with a median time for recurrent VTE of 33 days. The recurrence rate of VTE was estimated to 7.8% (95% CI 4.9-12.5) for patients classified at high risk of recurrence according to the Ottawa score (score ≥ 1) compared to 3.8% (95%CI 1.6-8.9) for other patients (Ottawa score &lt; 1). AUC of the Ottawa score was 0.60 (95% CI 0.55-0.65). In multivariable analysis, none of the potential risk factors for recurrent VTE was significantly associated with recurrent VTE at 6 months. During the 6 months treatment period, 15 patients had a major bleeding and 2 patients experienced a HIT. At 3 and 6 months, 104 and 144 patients had died yielding a cumulative incidence of 26.1%, (95% CI 21.8-30.4) and 37.8% (95% CI 32.8-42.9), respectively. The main cause of death was underlying cancer. Conclusion In this prospective cohort of patients with cancer receiving LMWH for VTE, the Ottawa score did not accurately predict recurrent VTE. No other clinical predictor of recurrent VTE was identified in this study. Disclosures Meyer: Bayer: Other: travel support; LEO pharma: Other: travel support, Research Funding; SANOFI: Other: travel support, Research Funding; BMS-Pfizer: Other: travel support, Research Funding; Boehringer Ingelheim: Research Funding. Girard:Leo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Scotté:LEO Pharma A/S: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Tesaro: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; MSD: Honoraria, Research Funding, Speakers Bureau; Pierre Fabre Oncology: Honoraria, Research Funding, Speakers Bureau. Lamblin:Leo Pharma: Employment. Laporte:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boston scientific: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo-Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Evaluation of Cytogenetic Stratifications in Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1763-1763
Author(s):  
Lucia Masarova ◽  
Prithviraj Bose ◽  
Naveen Pemmaraju ◽  
Zeev E. Estrov ◽  
Lingsha Zhou ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromosome 1 ◽  
Trisomy 8 ◽  
Advisory Committees ◽  
High Risk Patients ◽  
Single Deletion ◽  
Risk Patients ◽  
Very High

Abstract Introduction: The revised cytogenetic risk stratification of patients with primary myelofibrosis (PMF) divided patients into 3 prognostic categories, with additional new category of very high risk patients (VHR). This score should enhance traditional classification incorporated in the Dynamic International Prognostic Scoring System-Plus (DIPPS-Plus). Objective: To evaluate the prognostic utility of cytogenetic stratifications (DIPSS-Plus and the revised cytogenetic model) in patients with PMF referred to our institution between 1984 and 2016. Methods: We retrospectively reviewed the charts of 883 patients with PMF with available cytogenetic analysis at the time of referral to our institution (> 10 metaphases). Cytogenetic was reported according to the International System for Human Cytogenetic Nomenclature. Patients were classified into cytogenetic risks based on DIPSS-Plus (Gangat, JCO, 2011), and the revised cytogenetic model (Tefferi, Leukemia, 2017). Overall survival (OS) was estimated using the Kaplan-Meier method, and groups were compared by the log rank test. Impact of cytogenetic abnormalities on OS was also evaluated by comparing them against patients with diploid karyotype using stepwise Cox regression. Results: Median age was 66 years (range, 27-88), and 64% of patients were male. The distribution of DIPSS scores was as follows: 8% low, 48% intermediate 1, 44% intermediate 2 and 14% high. OS in each DIPSS category was 53, 46, 26, 15 months (p<0.001). The JAK2, MPL and CALR mutation was present in 55% (n=486), 6% (n=50), and 7% (n=64). Overall, 563 (64%) patients had diploid karyotype. The most frequent abnormal karyotypes were single 20q- (n=68, 8%), single 13q- (n=40, 4.5%), and ≥3 abnormalities (Abn; complex karyotype, CK, n=52, 6%). Among patients with CK, 27 (52%) pts had VHR Abn. After a median follow-up of 22.4 months (range, 0.5-251); 708 (80%) of patients died. Eighty five patients (10%) developed acute leukemia, 39% of these patients had CK. According to DIPSS-plus, patients were stratified into favorable (FAV, n=758, 86%) and unfavorable (UNF, n=126, 14%) category with distinct median OS of 35 months (range, 31-39), and 17 months (range, 11.6-22), p < 0.001 (HR 1.37, [95% CI 1.11-1.7]). Three year OS was 49% and 32%, respectively (Figure 1a). The revised cytogenetic stratification classified patients into favorable (n=687, 78%), unfavorable (n=151, 17%), and VHR (n=47, 5%) with respective OS of 35, 32 and 10 months (overall p<0.001, FAV vs UNF p= 0.8; Figure 1b); similar between patients in favorable and unfavorable groups. Three year OS for each group was 49%, 46% and 12%, respectively. OS of patients with individual cytogenetics (as used in the revised classification) is depicted in Table. Patients with single deletion 13q have significantly inferior OS than the remaining patients in FAV group. Patients with sole abnormality of chromosome 1 and trisomy 9 had the longest OS within the FAV group, but without reaching a statistical significance. Similarly, patients with sole trisomy 8, sole deletion 7q/5q, and other sole Abn not included elsewhere, had inferior OS when compared to the remaining patients in UNF group (Table 1). After re-grouping patients with different OS from FAV and UNF groups, we have noticed an intermediate group of patients containing the above mentioned Abn with distinctly different OS from FAV and UNF group of 24 months (range, 14.5-33; Figure 1c). Conclusions: Results from our cohort of 883 PMF patients did not confirm better discriminatory power of revised cytogenetic stratification model when compared to the DIPSS-Plus, as it failed to differentiate different OS between favorable and unfavorable groups. In our cohort, patients with single deletion 13q, single trisomy 8, and abnormalities of 5q/7q have superior OS to very high risk patients, but inferior to all remaining patients. Because the revised cytogenetic stratification has been already incorporated into newer complex molecular prognostic models of patients with PMF (MIPSSversion2.0, GIPSS), its further validation is warranted. Table Abbr.: Chr, chromosome, del, deletion, DUP, duplication, transl, translocation, excl, excluding; ¥OTHER solo: INV(9) in [3], Abn chr. 11, 12, 16, 17, 18 (mostly deletion of p/q arms, or addition) [7]; VHR = very high risk (-7; inv(3)/3q21; i(17q); 12p-/12p11.2; 11q-/11q23; autosomal trisomies excl. +8/+9). Disclosures Bose: Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Research Funding. Pemmaraju:plexxikon: Research Funding; cellectis: Research Funding; Affymetrix: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding. Cortes:novartis: Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

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