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The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Ohio State 2016ASH Review: Benign Hematology
Spero R. Cataland, M.D.Professor of Clinical Internal MedicineDivision of HematologyOhio State University
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
SUSTAIN: A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 12-Month Study to Assess Safety and Efficacy of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises
Kenneth I. Ataga, MD, Abdullah Kutlar, MD, Julie Kanter, MD, Darla Liles, MD, Rodolfo Cancado, M.D., Ph.D., João Friedrisch, MD, PhD, Troy H. Guthrie, MD, Jennifer Knight-Madden, MBBS, PhD, Ofelia A. Alvarez, MD, Victor R. Gordeuk, MD, Sandra Gualandro, MD, PhD,MarinaPereira Collela, MD, PhD, Wally R. Smith, MD, Scott A. Rollins, PhD, Jonathan W. Stocker, PhD and Russell P. Rother, PhD
Adhesive interactions involving SS RBCs. (A) Multiple interactions between SS RBCs and endothelial cells, extracellular matrix, and plasma proteins.
Marilyn J. Telen Blood 2016;127:810-819
©2016 by American Society of Hematology
Double-blind, placebo-controlled, multinational study 16 to 65 years of age Diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia or HbSβ+ thalassemia) 2 to 10 SCPC in the previous 12 months. Patients receiving HU or erythropoietin eligible
On therapy for at least 6 months and dose was stable for at least 3 months.
Patients were randomized to receive placebo, 2.5 mg/kg or 5.0 mg/kg SelG1 Initial dose, dose 14 days later, and then every 4 weeks through week 50
Primary Endpoint: Annual rate of SCPC in the 5.0 mg/kg SelG1 group vs. placebo
Secondary Endpoints: Days hospitalized, time to 1st and 2nd SCPC Number of uncomplicated SCPC
4
Study Design/Eligibility Criteria
Sustain Study Results
Ataga KI et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1611770
Kaplan–Meier Curve for the Median Times to the First Sickle Cell–Related Pain Crises
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
A Prospective, Randomized Study of Cyclosporine or Corticosteroids as an Adjunct to Plasma Exchange for the Treatment of Acquired TTP
Spero R. Cataland, Shangbin Yang, Camila Masias, Peter J. Kourlas, Michael McGookey, Lauren Jay, Haiwa Wu, Susan Geyer, James N. George, and Haifeng Wu*
*Deceased
Study based upon results of two single arm studies of cyclosporine (CSA) or prednisone (Pred) as adjuncts to plasma exchange therapy (PEX)1
Exacerbation rates in each study1 :− Pred/PEX 6/10 (60%)− CSA/PEX: 0/8 (0%)
Study objectives: Primary:
Exacerbation rate CSA/PEX v. Pred/PEX − Recurrent thrombocytopenia requiring PEX in <30 d. after the
last PEX procedure Secondary
Comparative effect on: − ADAMTS13 activity, inhibitor titer, and inhibitor concentration
7
Study Rationale and Objectives
1. Cataland et al. BJH October 2006. p.146-9.
8
Study Methods: Treatment Plan
EligibilityClinical diagnosis of Acquired TTP
-(MAH, Platelet <100K)
-Additional explanations excluded
-Serum Creatinine <2.5 mg/dl
Plasma Exchange(1.0 Plasma Volume)
Daily until Remission:− Normal platelet count
and LDH
Cyclosporine
2-3 mg/kg/day for 6 months
Prednisone
1 mg/kg/day for 1 month
(tapered over 4 weeks)
+
+
9
Clinical and ADAMTS13 Outcome Data
* One death in each arm of study** 2 patients refractory to prednisone crossed over to CSA arm
10
Results: Anti-ADAMTS13 IgG : First 30 Days and Beyond
0.0
10.0
20.0
30.0
40.0
50.0
60.0
Pre‐Treat week 1 week 2 week 3 week 4
Anti‐AD
AMTS13
IgG
(1.1‐11.8 U/m
l)
CSA
Prednisonep=0.339
p=0.342p=0.029
p=0.028 p=0.039
*Week 1 sample at least 5 days after last PEX procedure
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
1 2 3 4 5 6
Anti‐AD
AMTS13
IgG
(Normal 1.1‐11.8)
Months Since Remission
CSA
Prednisone
p=0.039
p=0.086
p=0.480 p=0.865 p=0.850 p=0.302
Study confirms the role of immune suppressive therapy with Pred as an adjunct to PEX
No significant difference in the exacerbation rates between the CSA/PEX and Pred/PEX treated patients
− Suggestion of lower exacerbation rate on Pred/PEX arm− Increases in ADAMTS13 activity and decline in anti-ADAMTS13 antibodies significantly
better with Prednisone v. CSA over the first 30 days
11
Conclusions
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Splenectomy or Rituximab in Steroid-Refractory Immune Thrombocytopenia (ITP): The Mayo Clinic Experience
William A. Hammond, MD, Elisa M. Rodriguez, Zhuo Li, M.S, Bhagirathbhai Dholaria, MBBS, Amanda Shreders, MD, Prakash Vishnu, MD and Candido E. Rivera, MD
Study Design
Retrospective cohort study of adults with ITP Treated at one of the Mayo Clinic sites (Arizona,
Florida, or Minnesota) between 1990 – 2015 Received second-line treatment with either rituximab
or splenectomy Primary end-points were freedom from relapse after
2nd and 3rd line treatment with rituxumab or splenectomy
Response = platelet count >30,000
Results
222 ITP patients: 191 primary and 31 secondary Splenectomy patients were younger at diagnosis (49
vs 60 years, P=0.003) and time of 2nd line treatment (51.5 vs 61 years, P=0.018)
Splenectomy patients: More likely to achieve CR (86.6% vs 44%, P<0.0001) Higher 5y freedom from relapse (53.57% v. 14.96%,
P<0.0001).
Data remained similar when primary ITP and secondary ITP were considered seperately
Splenectomy v. Rituximab: Long-Term Outcomes
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Rivaroxaban versus Fondaparinux in the Treatment of Superficial Vein Thrombosis – the Surprise Trial
Jan Beyer-Westendorf, MD, Sebastian Schellong, MD, Horst Gerlach, MD, KatjaJersemann, Eberhard Rabe, MD, Kurtulus Sahin and Rupert Bauersachs, MD, PhD
Study design
Randomized, open-label blinded evaluation, non-inferior comparison
Inclusion: Patients with SVT at high risk of VTE complications Supragenual SVT + Age > 65, male, h/o VTE, cancer,
autoimmune, non varicose veins Rivaroxaban 10 mg qd vs fondaparinux 2.5 mg qd for 45 d. Observed until 90 days
Primary efficacy outcome: Composite endpoint of DVT, PE, SVT progression and
recurrence, all cause mortality at day 45 Primary safety outcome: Major bleeding during treatment by ISTH criteria
Results
N=472 Rivaroxaban (n=211), Fondaparinux (n=224)
Mean age 60.3 years; 60.4% female, Mean treatment duration was 44 days
Day 45 primary efficacy outcome: 3.3% (95%-CI 0.90; 5.73) on rivaroxaban 1.8% (95%-CI 0.05; 3.52) on fondaparinux
p-value for non-inferiority 0.025
No major bleeding occurred Non-major, clinically relevant bleeding were 2.5% (R) vs. 0.4% (F) at d 45.
Results
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Reversal of Betrixaban-Induced Anticoagulation in Healthy Volunteers By Andexanet Alfa
Mark Crowther, MD, Genmin Lu, PhD, Janet M. Leeds, PhD, Joyce Lin, BS, Pamela B. Conley, PhD, Alexander Gold, MD, Stuart J. Connolly, MD and John T. Curnutte, MD, PhD
Connolly SJ et al. NEJM 2016;375:1131-1141.
Andexanet alfa
• The ANNEXA-4 study (The Ability of Andexanet Alfa to Reverse the Anticoagulant Activity-4) study is to evaluate the efficacy and safety of andexanet for serious bleeding in patients on rivaroxban, apixaban, edoxaban, or enoxaparin
• Dose: a bolus followed by 2 hr infusion• Anti-Xa activity decreased by ~90% after infusion, with 79 achieving
effective hemostasis.
Anti–Factor Xa Activity and Percent Change from Baseline in Patients Receiving Rivaroxaban and Apixaban (Efficacy Population).
Connolly SJ et al. N Engl J Med 2016;375:1131-1141
• ANNEX-4 study, Multicenter, open label, ongoing study
• N = 67 with major bleeding who were on rivaroxaban, apixaban, edoxaban, or enoxaparin within the past 18 hr
• Effective hemostasis in 79%
Reversal of Betrixaban-Induced Anticoagulation
Betrixaban, a direct FXa inhibitor, recently completed a large Phase 3 clinical trial in acute medically ill patients (APEX)
This is a study to test the reversal effects of andexanet again the new DOAC betrixaban in healthy volunteers Andexanet (n=13) v. placebo (n=6) Followed day 7 of betrixaban to steady state (80 mg/d)
Cohort 1: Andexanet 800 mg bolus 3 hours after last dose of betrixaban v. placebo Cohort 2: Andexanet 800 mg bolus 4 hours after last dose + 2 hr infusion (8mg/min) v. placebo
As prior studies on other anti-Xa inhibitors andexanet significantly and rapidly: Reduced the anti-Xa level, drug (betrixaban) concentrations, restored thrombin generation Could be a universal antidote for all four direct FXa inhibitors
apixaban, rivaroxaban, edoxaban, and betrixaban as well as indirect FXa inhibitors
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Association of BW with Thromboembolic and Bleeding Outcomes in Phase III Randomized Controlled Trials of Direct Oral Anticoagulants: Systematic Review and Meta-Analysis
Kochawan Boonyawat, MD, Francois Caron, MD, Ang Li, MD, Chatree Chai-Adisaksopha, MD, Wendy Lim, MD, Iorio Alfonso, MD, PhD, Renato Delascio Lopes, MD, PhD, David A Garcia, MD and Mark Crowther, MD
Thrombotic outcomes – High body weight
• Meta Analysis of phase III RCT using DOACs for the prevention of stroke in AF and acute VTE
• Data on thromboembolic complications including stroke and VTE, and bleeding complications and comparator arm abstracted
• 9 Phase III RCT included:
Summary and Limitations
The “Obesity paradox” Patients with low body weight had an increased risk of
VTE The subgroup of AF patients with high body weight with
decreased risk of VTE There was no significant difference in the bleeding risk
in both low and high weight groups There was no interaction between types of
anticoagulation and thromboembolic outcomes This study supports fixed dose effects of DOACs Limitations: study level meta-analysis of subgroups Few extremely high weight patients