Booth # 503
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CLINICAL NEWS |
testing ), the recommendation changes as prevalence changes : “ For low pre-test probability ( 5 % instead of 50 %), i . e ., for patients with a low likelihood of the disease , the panel recommended starting with a D- dimer test , followed by additional testing if the D-dimer is positive ,” Dr . Crowther explained . “ For high pre-test probability , the strategies could start with a CTPA , followed by additional testing if the CTPA is negative .” |
Cancer-Associated VTE : No Routine Thromboprophylaxis Gary H . Lyman , MD , MPH , from the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle , tackled a complicated issue : whether ambulatory patients with cancer who are receiving chemotherapy should also receive VTE prophylaxis .
This was one of the clinical areas in which panelists were granted abundant
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clinical trial data to consider , including 17 randomized , controlled trials published in the past decade . “ For all patients across the trials , we observed an average VTE risk of 6 to 7 percent in the control group ,” Dr . Lyman reported , “ whereas risk in the low-molecular-weight heparin ( LMWH ) group was about half of that , for a relative risk of 0.55 .”
However , he added , absolute risk difference was less clear-cut , based on the
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low baseline risk of VTE among the study populations . This risk also varies according to cancer subtype , he noted .
After reviewing the available evidence , the panel recommended against routine thromboprophylaxis for most patients in this setting , but with important exceptions . “ This is a strong recommendation for patients who are considered to be at low risk for VTE , a conditional recommendation against the routine prophylaxis in those at intermediate
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VTE Prophylaxis in Surgical Patients : No to IVC Filters David R . Anderson , MD , from Dalhousie University in Halifax , Nova Scotia , discussed a recommendation for preventive anticoagulation in patients with VTE who require major surgery , specifically when and in whom inferior vena cava ( IVC ) filters should be used .
IVC filters might be considered as prophylaxis , rather than standard anticoagulation in patients undergoing major surgery , because “ anticoagulation may be contraindicated because of bleeding risk , and mechanical prophylaxis may not be feasible because of injury ,” he explained .
Compared with the limited data from randomized clinical trials , observational studies provided “ considerably more information on this recommendation ,” according to Dr . Anderson . “ Overall mortality was actually higher in patients , or observed to be higher in patients , who had IVC filters ,” he said , “ with a 1.5 percent absolute increased risk of death .”
Unprovoked VTE : Patient and Provider Choice Thomas L . Ortel , MD , PhD , of Duke University in Durham , North Carolina , discussed a recommendation for the treatment of patients with an unprovoked VTE who have completed an initial course of therapy ( ≥3-6 months ). In this setting , “ the question is , if you are going to use a direct oral anticoagulant ( DOAC ) for indefinite therapy , would a lower dose be better or equivalent to a standard dose ?” Dr . Ortel explained .
To answer this question , panelists reviewed evidence from two randomized clinical trials comparing DOACs against aspirin for extended anticoagulation . “ When you look at the anticipated absolute effect of a lower-dose DOAC , the risks with the standard dose are comparatively fairly low for each of our outcomes of interest ,” Dr . Ortel reported . The risks of mortality and deep vein thrombosis were slightly lower in the lower-dose group , but the risk of non-fatal PE was higher .”
Given the small observed differences between low- and standard-dose DOACs , the panel allowed for more flexibility in this recommendation . In its eventual , conditional recommendation , the panel suggested using either dose for indefinite therapy , based on patients ’ and providers ’ values and preferences .
MCL-1 dependence may drive progression of AML 1 , 2
Acute myeloid leukemia ( AML ) is associated with high mortality and is challenging to treat , with an overall 5-year survival rate of 27 %. 4 , 5 Standard therapies often fail to achieve the goal of inducing complete remission in 25 %– 50 % of patients , and relapse is common even in patients who have an initial response to treatment . 1 , 5 Disease progression and treatment resistance in a subset * of AML have been associated with a key anti-apoptotic protein , myeloid cell leukemia 1 ( MCL-1 ). 1 , 2 This is referred to as MCL-1 dependence . 6 Understanding the role of MCL-1 can inform therapeutic targeting strategies in AML . 7
Learn more at www . toleropharma . com
MCL-1 , a BCL-2 family member , is an MCL-1 may have multiple roles in sustaining AML blasts 1 , 3
MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins . 8 In normal function , MCL-1 is essential for early embryonic development and for the survival of multiple cell lineages , including lymphocytes and hematopoietic stem cells . 3
However , in MCL-1 – dependent AML , MCL-1 has been shown to sustain the survival of AML cells , which may lead to relapse . 1 MCL-1 dependence is also associated with resistance to agents that otherwise have activity against leukemic blasts . 8
A key function of MCL-1 is to inhibit apoptosis 1
In addition , independently of its anti-apoptotic activity , MCL-1 has a role in mitochondrial function that may promote cancer cell survival and proliferation . 3 The antiapoptotic and mitochondrial functions of MCL-1 may synergize to promote tumor progression by inhibiting apoptosis and supporting proliferation . 3
* The prevalence of MCL-1 – dependent AML is under investigation .
in MCL-1 – dependent AML 1-3
Downregulation of MCL-1 to enable apoptosis of leukemic blasts may be a rational therapeutic strategy in MCL-1 – dependent AML 7
The activity of cyclin-dependent kinase 9 ( CDK9 ) is essential for the transcription of MCL-1 mRNA in leukemic blasts . 9 , 10
RNA polymerase II
Because of the short half-life of MCL-1 ( 2-4 hours ), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly . 11 CDK9 inhibition has been shown to block MCL-1 transcription , resulting in the rapid downregulation
8 , 12 , 13 of MCL-1 protein , thus triggering apoptosis .
If you have patients with AML , learn more about available clinical trials at the ASH Annual Meeting
Booth # 503
A matter of cell life and cell death
Tolero Pharmaceuticals , Inc . is a leader in developing novel therapeutics to inhibit biological drivers of hematologic and oncologic diseases by targeting pathways for gene transcription and drug resistance .
References : 1 . Glaser SP , Lee EF , Trounson E , et al . Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia . Genes Dev . 2012 ; 26 ( 2 ): 120-125 . 2 . Xiang Z , Luo H , Payton JE , et al . Mcl1 haploinsuffi ciency protects mice from Myc-induced acute myeloid leukemia . J Clin Invest . 2010 ; 120 ( 6 ): 2109-2118 . 3 . Perciavalle RM , Opferman JT . Delving deeper : MCL-1 ’ s contributions to normal and cancer biology . Trends Cell Biol . 2013 ; 23 ( 1 ): 22-29 . 4 . National Cancer Institute . Cancer stat facts : acute myeloid leukemia . https :// seer . cancer . gov / statfacts / html / amyl . html . Accessed July 29 , 2017 . 5 . Tallman MS , Gilliland DG , Rowe JM . Drug therapy for acute myeloid leukemia . Blood . 2005 ; 106 ( 4 ): 1154-1163 . 6 . Wei G , Margolin AA , Haery L , et al . Chemical genomics identifi es small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency . Cancer Cell . 2012 ; 21 ( 4 ): 547-562 . 7 . Bose P , Grant S . Mcl-1 as a therapeutic target in acute myelogenous leukemia ( AML ). Leuk Res Rep . 2013 ; 2 ( 1 ): 12-14 . 8 . Thomas D , Powell JA , Vergez F , et al . Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription . Blood . 2013 ; 122 ( 5 ): 738-748 . 9 . Chen R , Keating MJ , Gandhi V , Plunkett W . Transcription inhibition by fl avopiridol : mechanism of chronic lymphocytic leukemia cell death . Blood . 2005 ; 106 ( 7 ): 2513-2519 . 10 . Ocana A , Pandiella A . Targeting oncogenic vulnerabilities in triple negative breast cancer : biological bases and ongoing clinical studies . Oncotarget . 2017 ; 8 ( 13 ): 22218-22234 . 11 . Gores GJ , Kaufmann SH . Selectively targeting Mcl-1 for the treatment of acute myelogenous leukemia and solid tumors . Genes Dev . 2012 ; 26 ( 4 ): 305-311 . 12 . Morales F , Giordano A . Overview of CDK9 as a target in cancer research . Cell Cycle . 2016 ; 15 ( 4 ): 519-527 . 13 . Yin T , Lallena MJ , Kreklau EL , et al . A novel CDK9 inhibitor shows potent antitumor effi cacy in preclinical hematologic tumor models . Mol Cancer Ther . 2014 ; 13 ( 6 ): 1442-1456 .
Tolero Pharmaceuticals is a registered trademark of Tolero Pharmaceuticals , Inc . in the US . © 2017 Boston Biomedical , Inc . All rights reserved . PM-ALV-0002 10 / 2017
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