ASCO Review Benign Hematology

Tzu-Fei Wang, M.D. Assistant Professor of Medicine

Division of hematology 6/13/2015

I have no financial conflicts to disclose.

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

Cancer and venous thrombosis

http://www.medicinenet.com/deep_vein_thrombosis_dvt_pictures_slideshow/article.htm

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 OD LITE N=200

CANTHANOX N=146

Enoxaparin 1.5 mg/kg OD

Control Group

CLOT N=672

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

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

Results

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

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)

Target-specific (novel) oral anticoagulants (TSOACs)

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

Mechanism of action

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

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%

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

Intracranial bleeding events comparing TSOACs with VAKs

Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458 ©2014 by American Society of Hematology

Major GI bleeding events comparing TSOACs with VAKs

Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458 ©2014 by American Society of Hematology

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

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

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)

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.

Siegal D M et al. Blood 2014;123:1152-1158 ©2014 by American Society of Hematology

Proposed strategy for management of TSOAC-associated bleeding

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)

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

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 mo 24

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)

Duration of anticoagulation

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.

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

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

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.

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

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

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

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.

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

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

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

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

• 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)

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

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