Spero R. Cataland, MD Professor of Clinical Internal Medicine The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

1. 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 Medicine
Division of Hematology
Ohio State University

2. 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,Marina
Pereira Collela, MD, PhD, Wally R. Smith, MD, Scott A. Rollins, PhD, Jonathan W. Stocker, PhD
and Russell P. Rother, PhD

3. 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

4.  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

5. 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

6. 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

7.  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. 8
Study Methods: Treatment Plan
Eligibility
Clinical 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. 9
Clinical and ADAMTS13 Outcome Data
* One death in each arm of study
** 2 patients refractory to prednisone crossed over to CSA arm

10. 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‐ADAMTS13 IgG
(1.1‐11.8 U/ml)
CSA
Prednisone
p=0.339
p=0.342
p=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‐ADAMTS13 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

11.  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

12. 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

13. 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

14. 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

15. Splenectomy v. Rituximab: Long-Term Outcomes

16. 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, Katja
Jersemann, Eberhard Rabe, MD, Kurtulus Sahin and Rupert Bauersachs, MD, PhD

17. 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

18. 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.

19. Results

20. 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

21. 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.

22. 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%

23. 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

24. 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

25. 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:

26. 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