ASCO Review Benign Hematology Tzu-Fei Wang, M.D. Assistant Professor of Medicine Division of hematology

1. ASCO Review
Benign Hematology
Tzu-Fei Wang, M.D.
Assistant Professor of Medicine
Division of hematology
6/13/2015

2. I have no financial conflicts to disclose.

3. Overview
 Cancer and Venous thromboembolic disease (VTE)
 Target-specific oral anticoagulants
 Duration of anticoagulation (if time permits)
 ASH Choosing Wisely Campaign

4. Cancer and venous
thrombosis
http://www.medicinenet.com/deep_vein_thrombosis_dvt_pictures_slideshow/article.htm

5. LMWH
Vitamin K antagonist (INR 2.0 to 3.0)
Dalteparin 200 IU/kg OD then ~150 IU/kg OD
5 – 7 days 1 month 3 months 6 months
Treatment of Acute VTE in Cancer
Tinzaparin 175 IU/kg ODLITE
N=200
CANTHANOX
N=146
Enoxaparin 1.5 mg/kg OD
Control
Group
CLOT
N=672

6. Randomized Trial of Long-Term Tinzaparin, a Low
Molecular Weight Heparin (LMWH), Versus Warfarin
for Treatment of Acute Venous Thromboembolism
(VTE) in Cancer Patients - the CATCH Study
Lee A, et al.
2014 ASH

7. Methods
 900 pt, 165 sites, 32 countries, 5 continents
 Tinzaparin arm (n=449), warfarin arm (n=451)
 Mean age 59 (18-89), 59% female, 77% ECOG
0-1, 23% ECOG 2
 Malignancy: 23% gyn, 13% colon, 12% lung,
9% breast, 10% heme, 55% metastatic
 Time in therapeutic for warfarin arm is 47%,
27% above and 26% below

8. Results
Figure. Cumulative incidence of recurrent VTE in the tinzaparin and warfarin groups

9. Conclusion
In patients with active cancer and acute venous
thromboembolism, tinzaparin:
 reduced the cumulative risk of recurrent VTE from
10.5% to 7.2% (HR 0.65; 0.41 to 1.03)
 significantly lowered the risk of symptomatic DVT by
52% (p=0.04)
 did not increase major bleeding despite full dose
 significantly reduced clinically relevant non-major
bleeding (p=0.03)

10. Target-specific (novel) oral
anticoagulants (TSOACs)

11. Target-specific oral anticoagulants
Dabigatran Rivaroxaban Apixaban Edoxaban
Mechanism of
action
direct thrombin
inhibitor
direct factor Xa
inhibitor
direct factor Xa
inhibitor
direct factor Xa
inhibitor
Bioavailability 6-7 % >80 % ~66 % 62%
Prodrug Yes No No No
T max 2 hrs 3 hrs 3-4 hrs 1.5 hrs
Half life 7-17 hrs 6-13 hrs 8-13 hrs 10-14 hrs
Dosing bid Once daily bid Once daily
Protein Binding 35 % 90 % 90 % 40-59%
Metabolism 80-85% renal
(activated by liver)
67% renal
33% fecal
25% renal
75% fecal
33% renal
Drug interaction p-glycoprotein
inducer/inhibitor
CYP 3A4
p-glycoprotein
CYP 3A4
p-glycoprotein
p-glycoprotein
Kaatz et al. Am J Hematol. 2012;87:S141-145

12. Mechanism of action
http://www.lookfordiagnosis.com/mesh_info.php?term=Anticoagulants&lang=1

13. Effectiveness of target-specific oral anticoagulants as compared with
vitamin K antagonists in the treatment of acute symptomatic venous
thromboembolism: a systematic review and meta‐analysis
Journal of Thrombosis and Haemostasis
Volume 12, Issue 3, pages 320-328,
N=24,455
2.0% 2.2%

14. Major bleeding events comparing target-
specific anticoagulants with VAKs
Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458
©2014 by American Society of Hematology
N=102,607

15. Intracranial bleeding events comparing
TSOACs with VAKs
Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458
©2014 by American Society of Hematology

16. Major GI bleeding events comparing TSOACs
with VAKs
Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458
©2014 by American Society of Hematology

17. Summary of VTE data
Drug Recurrent
Thrombosis
Major Bleeding Major and
CRNMB
Dabigatran Equal Equal Reduced
Rivaroxaban Equal Reduced Equal
Apixaban Equal Reduced Reduced
Edoxaban Equal Equal Reduced

18. FDA activity
Dabigatran
Pradaxa®
Rivaroxaban
Xarelto®
Apixaban
Eliquis®
Edoxaban
Savaysa®
VTE treatment FDA approved
4/7/2014
FDA approved
11/2/2012
FDA approved
8/22/2014
FDA approved
1/8/2015
VTE secondary
prevention
No FDA activity FDA approved
11/2/2012
FDA approved
8/22/2014
No FDA activity
Atrial fibrillation FDA approved
10/19/2010
FDA approved
11/4/2011
FDA approved
12/28/2012
FDA approved
1/8/2015
VTE prevention
(orthopedic
surgery)
No FDA activity FDA approved
7/1/2011
FDA approved
3/14/2014
No FDA activity

19. Dosage
Dabigatran
Pradaxa®
Rivaroxaban
Xarelto®
Apixaban
Eliquis®
Edoxaban
Savaysa®
VTE treatment 150 mg bid (CrCl >30
mL/min) after 5-10
days of parenteral
15 mg bid x 21 days
then 20 mg daily
10 mg bid x 7 days
then 5 mg bid
•60 mg daily
•30 mg daily (if CrCl
15–50, body weight
is <60 kg, or strong
p-GP inhibitors)
VTE secondary
prevention
N/A 20 mg daily 2.5 mg bid N/A
Atrial fibrillation •150 mg bid (CrCl
>30 mL/min)
•75 mg bid (CrCl 15-
30)
•20 mg daily (CrCl
>50 mL/min)
•15mg daily (CrCl 15-
50)
•5 mg bid
•2.5 mg bid (if ≥ 2
factors: age ≥80,
weight ≤60 kg, Cr
≥1.5 mg/dL)
•60 mg daily
•30 mg daily (if CrCl
15–50, body weight
is <60 kg, or strong
p-GP inhibitors)
Orthopedic VTE
prevention
N/A 10 mg daily 2.5 mg bid 30 mg daily (in
Japan)

20. Data on current indirect reversal Agents
Dabigatran Rivaroxaban Apixaban
Oral activated charcoal In vitro No data No data
Hemodialysis Human volunteers No data No data
Hemoperfusion with
activated charcoal
In vitro No data No data
FFP Mouse model No data No data
aFVIIa Rat and mouse model Rat and baboon model No data
3-factor PCC No data No data No data
4-factor PCC Human volunteers
(negative), rat, mouse, and
rabbit model
Human volunteers No data
aPCC Rat model Baboon model No data
Kaatz et al. Am J Hematol. 2012;87:S141-145.

21. Siegal D M et al. Blood 2014;123:1152-1158
©2014 by American Society of Hematology
Proposed strategy for management of TSOAC-associated
bleeding

22. Direct antidotes of TSOACs
IDARUCIZUMAB
(BI 655075)
ANDEXANET
(PRT064445)
ARIPAZINE (PER977)
Mechanism of action A humanized mouse
monoclonal antibody (Fab
fragment) directed against
dabigatran
A recombinant, modified
factor Xa molecule that sops
up the anti-Xa anticoagulant
A synthetic small molecule
(D-arginine compound) with
broad activity against
various anticoagulants
Drugs targeted against Dabigatran Apixaban, edoxaban,
rivaroxaban
Apixaban, edoxaban,
rivaroxaban, dabigatran,
heparin, LMWH
Status of clinical trials Phase III study of patients
ongoing (NCT02104947)
Three phase I studies in
healthy volunteers completed
(NCT01688830;
(NCT01955720;
NCT02028780)
FDA granted priority review to
the license application
4/23/2015
Phase II healthy volunteer
studies are ongoing
(NCT01758432;
NCT02207725;
NCT02220725)
A human volunteer study of
80 individuals showed
decrease in whote blood
clotting time, another
volunteer study ongoing
(NCT02207257)

23. TSOAC use in cancer patients (meta-analysis)
23 Chest. 2015;147(2):475-483. doi:10.1378/chest.14-0402
VTE recurrence
Major bleeding
N=1132

24. The PROBE study
 An international, phase IIIB, randomized, open-label, blind
evaluator study to evaluate the efficacy and safety of
dalteparin vs edoxaban in the treatment of VTE in cancer
patients
 Inclusion criteria
 Cancer patients (within 2 yr of diagnosis) with confirmed
proximal LE DVT or PE, plan for at least 6 months of
anticoagulation
 Exclude CrCL <30, plt <50,000, IVC filter or thrombectomy,
active bleeding, hepatitis
 Primary outcome: composite of recurrent VTE and major
bleeding at 12 mo24

25. Study Design
25
• Planned enrollment N=1000
• OSU is a study site and we are in the process of IRB application
• Anticipate to open for enrollment at our site in 3 months
• We welcome any of your patients that are interested in the study!
• All medications will be paid for by the study, with only 7 study visits in one
year (around every 3 months)

26. Duration of anticoagulation

27. Duration of anticoagulation
27
3 mo v.s. long term
6 wks v.s. 6 mo 3 mo v.s. 1 yr
Schulman S et al. N Engl J Med 1995;332:1661-1665.
Agnelli G et al. N Engl J Med 2001;345:165-169
Kearon C et al. N Engl J Med 1999;340:901-907.

28. Fig 1 Cumulative probability (top) and rate (bottom) of recurrent venous thromboembolism
(VTE) after stopping treatment according to initial length of treatment (adjusted for age, sex,
study, location of initial VTE, and presence of temporary risk factor.
Florent Boutitie et al. BMJ 2011;342:bmj.d3036
©2011 by British Medical Journal Publishing Group

29. Determining duration of anticoagulation
 Risk of recurrence
 circumstances of thrombosis (provoked vs unprovoked)
 patient characteristics (ie age, gender, hereditary
thrombophilia, etc.)
 utility of d-dimer
 utility of residual vein obstruction
 Risk of bleeding
 patient characteristics
 stability of anticoagulation
 Patient preferences

30. Predicting VTE recurrence –
MEN continue and HERDOO2
 Prospective cohort study (N=646, 11 centers, 3 counties, 2001-2006)
 Patients with first unprovoked VTE s/p anticoagulation x 5-7 mo
 Mean age 53 (18-95), 49% were female, mean f/u: 3.1 year
 High risk women with ≥ 2 of
 Hyperpigmentation
 Edema or Redness
 Vidas D-dimer >250 µg/L (on anticoagulation)
 Obesity (BMI>30)
 Older age (>65)
 Annual risk of recurrent VTE
 Man- 13.7% (95% CI 10.8-17%)
 High risk (≥2 risk factors) women- 14.1% (10.9-17.3%)
 Low risk (0-1 risk factors) women- 1.6% (0.3-4.6%)
 Conclusion: Women with low risk can safely discontinue anticoagulation, but Validation is needed
Rodger MA et al. CMAJ 2008;179(5):417-426.

31. Predicting VTE recurrence –
DASH score
 Retrospective pooled analysis (N=1818)
 Patients with first unprovoked VTE treated for at least 3
months of anticoagulation
31
 Risk factors (D2A1H1S-2)
 D-dimer (elevated after
stopping anticoagulation) +2
 Age (≤ 50yo) +1
 Sex (male) +1
 Hormonal therapy (VTE not
associated with H) -2
3.1%
9.3%
 Conclusion: In patients with DASH score ≤ 1, can stop
anticoagulation after 3 mo of treatment

32. The Vienna prediction model
(ng/mL)
Eichinger et al. J Am Heart Assoc. 2014 Jan 2;3(1):e000467.
http://cemsiis.meduniwien.ac.at/en/kb/science-
research/software/clinical-software/recurrent-vte/version-history
3 weeks after discontinuation of anticoagulation

33. Becattini C et al. N Engl J Med 2012; 366:1959-1967
Brighton TA et al. N Engl J Med 2012;367:1979-1987
ASA as secondary prevention of VTE

34. Effects of aspirin treatment on recurrent venous thromboembolism and other
outcomes after adjustment for baseline characteristics: age , sex, qualifying
event, body mass index, and duration of anticoagulation:
The INSPIRE Collaboration
John Simes et al. Circulation. 2014;130:1062-1071
Copyright © American Heart Association, Inc. All rights reserved.

35. Symptomatic Recurrent VTE or Related
Death - AMPLIFY-EXT
8.8%
1.7%
1.7%
Agnelli G, et al NEJM 2013;368(8):699-708
P<0.001
NNT = 14

36. MB or CRNMB- AMPLIFY-EXT
4.3%
3.2%
2.7%
Agnelli G, et al NEJM 2013;368(8):699-708
MB
0.1%
0.2%
0.5%
NNH=200

37. EISTEIN-CHOICE study
37
• A phase III, International, randomized, double-blind study, superiority design
• Inclusion: patients with confirmed symptomatic PE and/or DVT after completion of 6-12
months of anticoagulation
• Exclusion: CrCL<30ml/min, active bleeding, needing therapeutic anticoagulation,
concurrent use of CYP3A4 and p-gp inhibitors
• Planned enrollment: ~3000 patients
• Primary outcome: symptomatic recurrent VTE (efficacy), major bleeding (safety)
• Study duration:12 months, after 6 months, clinicians can decide to stop study
medications
• OSU has been selected as a site and plans to open in 6 months

38. ASH Choosing Wisely® Campaign (2013)
 A quality improvement initiative of the ABIM. The goal is to identify
medical practices that are not evidence based and may lead to adverse
outcomes, and to encourage physicians and patients to question such
tests, procedures and treatments.
 ASH identified five area in 2013:
 Don’t transfuse more than the minimum number of RBC necessary to
relieve symptoms of anemia or return to a safe Hgb range
 Don’t test for thrombophilia in adult patients with VTE in the setting of
major transient risk factors (surgery, trauma, prolonged immobility)
 Don’t use IVC filters routinely in patients with acute VTE
 Don’t administer plasma or PCC for non-emergent reversal of warfarin
 Limit surveillance CT scans in asymptomatic patients following curative-
intent treatment for aggressive lymphoma

39. • Duration of anticoagulation: Don’t treat with an anticoagulant for > 3
months in a patient with a first venous thromboembolic event (VTE)
occurring in the setting of a major transient risk factors.
• Sickle cell disease: Don’t routinely transfuse sickle cell patients for
chronic anemia or uncomplicated pain crisis without an appropriate
clinical indication.
• Don’t perform baseline or routine surveillance CT scans I patients with
asymptomatic, early-stage CLL.
• HIT: Do not test or treat for suspected HIT in patients with a low pre-
test probability of HIT”.
• ITP: Don’t treat patients with ITP in the absence of bleeding or a very
low platelet count.
ASH Choosing Wisely® Campaign (2014)

40.  The Hemostasis and Thrombosis Center (HTC), the sickle
cell program, and the TTP/aHUS program
 We continue to develop research programs in these areas
 We hope to provide our service to you whenever needed,
and welcome any discussions or referrals
The Ohio State University Benign
Hematology Program

41. Questions???
Email:
Tzu-Fei.Wang@osumc.edu
Phone: 614-293-9441